Trispecific proteins and methods of use

ABSTRACT

Provided herein are B cell maturation agent (BCMA) targeting trispecific proteins comprising a domain binding to CD3, a half-life extension domain, and a domain binding to BCMA. Also provided are pharmaceutical compositions thereof, as well as nucleic acids, recombinant expression vectors and host cells for making such BCMA targeting trispecific proteins. Also disclosed are methods of using the disclosed BCMA targeting trispecific proteins in the prevention, and/or treatment diseases, conditions and disorders.

CROSS-REFERENCE

This application is the continuation application of Ser. No. 16/159,554,filed Oct. 12, 2018, and claims the benefit of U.S. ProvisionalApplication No. 62/572,381 filed Oct. 13, 2017, all of which areincorporated by reference herein in their entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Oct. 11, 2018, isnamed 47517-723_201_SL.txt and is 752,020 bytes in size.

BACKGROUND OF THE INVENTION

Cancer is the second leading cause of human death next to coronarydisease. Worldwide, millions of people die from cancer every year. Inthe United States alone, cancer causes the death of well over ahalf-million people each year, with some 1.4 million new cases diagnosedper year. While deaths from heart disease have been decliningsignificantly, those resulting from cancer generally are on the rise. Inthe early part of the next century, cancer is predicted to become theleading cause of death.

Moreover, even for those cancer patients that initially survive theirprimary cancers, common experience has shown that their lives aredramatically altered. Many cancer patients experience strong anxietiesdriven by the awareness of the potential for recurrence or treatmentfailure. Many cancer patients experience significant physicaldebilitations following treatment.

Generally speaking, the fundamental problem in the management of thedeadliest cancers is the lack of effective and non-toxic systemictherapies. Cancer is a complex disease characterized by geneticmutations that lead to uncontrolled cell growth. Cancerous cells arepresent in all organisms and, under normal circumstances, theirexcessive growth is tightly regulated by various physiological factors.

SUMMARY OF THE INVENTION

The selective destruction of an individual cell or a specific cell typeis often desirable in a variety of clinical settings. For example, it isa primary goal of cancer therapy to specifically destroy tumor cells,while leaving healthy cells and tissues intact and undamaged. One suchmethod is by inducing an immune response against the tumor, to makeimmune effector cells such as natural killer (NK) cells or cytotoxic Tlymphocytes (CTLs) attack and destroy tumor cells.

Provided herein is a B cell maturation agent (BCMA) binding trispecificprotein that comprises: (a) a first domain (A) which specifically bindsto human CD3; (b) a second domain (B) which is a half-life extensiondomain; and (c) a third domain (C) which specifically binds to BCMA,wherein the domains are linked in the order H2N-(A)-(C)-(B)-COOH,H2N-(B)-(A)-(C)-COOH, H2N-(C)-(B)-(A)-COOH, H2N-(C)-(A)-(B)-COOH,H2N-(A)-(B)-(C)-COOH, or H2N-(B)-(C)-(A)-COOH, wherein the domains arelinked by linkers L1 and L2.

In some instances, the first domain comprises a variable light domainand variable heavy domain, each of which is capable of specificallybinding to human CD3. The first domain can be humanized or human.

In some instances, the second domain binds albumin. The second domaincan comprise a single chain variable fragment (scFv), a variable heavydomain (VH), a variable light domain (VL), a single chain antibodybinding domain devoid of light chain (a VHH domain), a peptide, aligand, or a small molecule.

The third domain is, in some cases, a single chain antibody bindingdomain devoid of light chain (a VHH domain), a scFv, a VH domain, a VLdomain, a non-Ig domain, a ligand, a knottin, or a small molecule entitythat specifically binds to BCMA. In some non-limiting instances, thethird domain comprises a VHH domain.

In some instances, the first domain, the second domain, and the thirddomain are independently humanized or human.

Provided herein is a BCMA binding trispecific protein where the VHHdomain comprises complementarity determining regions CDR1, CDR2, andCDR3, wherein (a) the amino acid sequence of CDR1 is as set forth inX₁X₂X₃X₄X₅X₆X₇PX₈G (SEQ ID NO: 1), wherein X₁ is T or S; X₂ is N, D, orS; X₃ is I, D, Q, H, V, or E; X₄ is F, S, E, A, T, M, V, I, D, Q, P, R,or G; X₅ is S, M, R, or N; X₆ is I, K, S, T, R, E, D, N, V, H, L, A, Q,or G; X₇ is S, T, Y, R, or N; and X₈ is M, G, or Y; (b) the amino acidsequence of CDR2 is as set forth in AIX₉GX₁₀X₁₁TX₁₂YADSVK (SEQ ID NO:2), wherein X₉ is H, N, or S; X₁₀ is F, G, K, R, P, D, Q, H, E, N, T, S,A, I, L, or V; X₁₁ is S, Q, E, T, K, or D; and X₁₂ is L, V, I, F, Y, orW; and (c) the amino acid sequence of CDR3 is as set forth inVPWGX₁₃YHPX₁₄X₁₅VX₁₆ (SEQ ID NO: 3), wherein X₁₃ is D, I, T, K, R, A, E,S, or Y; X₁₄ is R, G, L, K, T, Q, S, or N; X₁₅ is N, K, E, V, R, M, orD; and X₁₆ is Y, A, V, K, H, L, M, T, R, Q, C, S, or N.

In one embodiment, the CDR1 does not comprise an amino acid sequence ofSEQ ID NO: 599. In one embodiment, the CDR2 does not comprise an aminoacid sequence of SEQ ID NO: 600. In one embodiment, the CDR3 does notcomprise an amino acid sequence of SEQ ID NO: 601. In one embodiment,the CDR1 and CDR2 do not comprise amino acid sequences of SEQ ID NO: 599and 600, respectively. In one embodiment, the CDR1 and CDR3 do notcomprise amino acid sequences of SEQ ID NO: 599 and 601, respectively.In one embodiment, the CDR2 and CDR3 do not comprise amino acidsequences of SEQ ID NO: 600 and 601, respectively. In one embodiment,the CDR1, CDR2 and CDR3 do not comprise amino acid sequences of SEQ IDNO: 599, 600 and 601, respectively.

Provided herein is a BCMA binding trispecific protein, where the VHHdomain comprises the following formula: f1-r1-f2-r2-f3-r3-f4; wherein,r1 is SEQ ID NO: 1; r2 is SEQ ID NO: 2; and r3 is SEQ ID NO: 3; andwherein f₁, f2, f3 and f4 are framework residues selected so that saidprotein is from about eighty percent (80%) to about 99% identical to theamino acid sequence set forth in SEQ ID NO: 598 or 346. Provided hereinis a BCMA binding trispecific protein, where the VHH domain comprisesthe following formula: f1-r1-f2-r2-f3-r3-f4; wherein, r1 is SEQ ID NO:1; r2 is SEQ ID NO: 2; and r3 is SEQ ID NO: 3; and wherein f₁, f2, f3and f4 are framework residues selected so that said protein is fromabout 80% to about 90% identical to the amino acid sequence set forth inSEQ ID NO: 598 or 346. In one embodiment, the amino acid sequence of thesingle domain BCMA binding protein does not comprise SEQ ID NO: 598.

In some non-limiting examples, r1 comprises an amino acid sequence setforth as any one of SEQ ID NOs: 4-117.

In some non-limiting examples, r2 comprises an amino acid sequence setforth as any one of SEQ ID NOs: 118-231.

In some non-limiting examples, r3 comprises an amino acid sequence setforth as any one of SEQ ID NOs: 232-345.

In other non-limiting examples, the protein comprises an amino sequenceset forth as any one of SEQ ID NOs: 346-460.

In a single domain BCMA binding protein, f1 comprises, in someinstances, SEQ ID NO: 461 or 462.

In a single domain BCMA binding protein, f2 comprises, in someinstances, SEQ ID NO: 463.

In a single domain BCMA binding protein, f3 comprises, in someinstances, SEQ ID NO: 464 or 465.

In a single domain BCMA binding protein, wherein f4 comprise, in someinstances, SEQ ID NO: 466 or 467.

In one non-limiting example, r1 comprises SEQ ID NO: 76, 114, 115, 116or 117. In one non-limiting example, r1 comprises SEQ ID NO: 76.

In one non-limiting example, r1 comprises SEQ ID NO: 76, r2 is SEQ IDNO: 190, and r3 is SEQ ID NO: 304.

In one non-limiting example, r1 comprises SEQ ID NO: 114, r2 comprisesSEQ ID NO: 228 and r3 comprises SEQ ID NO: 342.

In one non-limiting example, r1 comprises SEQ ID NO: 115, r2 comprisesSEQ ID NO: 229 and r3 comprises SEQ ID NO: 343.

In one non-limiting example, r1 comprises SEQ ID NO: 117, r2 comprisesSEQ ID NO: 231 and r3 comprises SEQ ID NO: 345.

In one non-limiting example, r1 comprises SEQ ID NO: 116, r2 comprisesSEQ ID NO: 230 and r3 comprises SEQ ID NO: 344.

The third domain, in some cases, is a human VHH domain, a humanized VHHdomain, an affinity matured VHH domain, or a combination thereof.

The BCMA binding trispecific protein, in some instances, has anelimination half-time of at least 12 hours, at least 20 hours, at least25 hours, at least 30 hours, at least 35 hours, at least 40 hours, atleast 45 hours, at least 50 hours, or at least 100 hours.

Provided herein is a BCMA binding trispecific protein that is a VHHdomain, where the VHH domain comprises a CDR1, a CDR2, and a CDR3, andwherein the protein comprises the sequence set forth as SEQ ID NO: 346or 598, wherein one or more amino acid residues selected from amino acidpositions 26, 27, 28, 29, 30, 31, 32 and/or 34 of CDR1; positions 52,54, 55 and/or 57 of CDR2; and positions 101, 105, 106 and/or 108 of CDR3are substituted, wherein amino acid position 26, if substituted, issubstituted with S; amino acid position 27, if substituted, issubstituted with D or S; amino acid position 28, if substituted, issubstituted with D, Q, H, V, or E; amino acid position 29, ifsubstituted, is substituted with S, E, A, T, M, V, I, D, Q, P, R, or G;amino acid position 30, if substituted, is substituted with M, R, or N;amino acid position 31, if substituted, is substituted with K, S, T, R,E, D, N, V, H, L, A, Q, or G; amino acid position 32, if substituted, issubstituted with T, Y, R, or N; amino acid position 34, if substituted,is substituted with G or Y; amino acid position 52, if substituted, issubstituted with N or S; amino acid position 54, if substituted, issubstituted with G, K, R, P, D, Q, H, E, N, T, S, A, I, L, or V; aminoacid position 55, if substituted, is substituted with Q, E, T, K, or D;amino acid position 57, if substituted, is substituted with V, I, F, Y,or W; amino acid position 101, if substituted, is substituted with I, T,K, R, A, E, S, or Y; amino acid position 105, if substituted, issubstituted with G, L, K, T, Q, S, or N; amino acid position 106, ifsubstituted, is substituted with K, E, V, R, M, or D; and amino acidposition 108, if substituted, is substituted with A, V, K, H, L, M, T,R, Q, C, S, or N. In one non-limiting example, the VHH domain is human,humanized, affinity matured, or a combination thereof.

Provided herein is a BCMA binding trispecific protein, where the thirddomain binds to a human BCMA protein that comprises a sequence set forthas SEQ ID NO: 468. In some instances, the third domain binds to anepitope of BCMA, wherein said epitope comprises the extracellular domainof BCMA. In some instances, the third domain binds to an epitope ofBCMA, wherein said epitope comprises amino acid residues 5-51 of SEQ IDNO: 468.

In such BCMA binding trispecific proteins, linkers L1 and L2 are eachindependently selected from (GS)_(n) (SEQ ID NO: 472), (GGS)_(n) (SEQ IDNO: 473), (GGGS)_(n) (SEQ ID NO: 474), (GGSG)_(n) (SEQ ID NO: 475),(GGSGG)_(n) (SEQ ID NO: 476), (GGGGS)_(n) (SEQ ID NO: 477), (GGGGG)_(n)(SEQ ID NO: 478) or (GGG)_(n) (SEQ ID NO: 479) wherein n is 1, 2, 3, 4,5, 6, 7, 8, 9, or 10.

In one non-limiting example, in such BCMA binding trispecific proteinsthe linkers L1 and L2 are each independently (GGGGS)₄ (SEQ ID NO: 480)or (GGGGS)₃ (SEQ ID NO: 481).

The domains of a BCMA binding trispecific protein can be linked in theorder H₂N-(C)-(B)-(A)-COOH.

In some instances, a BCMA binding trispecific protein is less than about80 kDa. In other instances, a BCMA binding trispecific protein can beabout 50 to about 75 kDa. In other instances, a BCMA binding trispecificprotein is less than about 60 kDa.

A BCMA binding trispecific protein described herein, in some instances,have an elimination half-time of at least about 50 hours, about 100hours or more.

A BCMA binding trispecific protein, in some instances, exhibit increasedtissue penetration as compared to an IgG to the same BCMA.

A BCMA binding trispecific protein, in some instances, comprises anamino acid sequence selected from the group consisting of SEQ ID NO:483-597. A BCMA binding trispecific protein, in some instances,comprises an amino acid sequence as set forth in SEQ ID NO: 520.

Provided herein in one embodiment is a B cell maturation agent (BCMA)binding trispecific protein comprising: (a) a first domain (A) whichspecifically binds to human CD3; (b) a second domain (B) which is ahalf-life extension domain; and (c) a third domain (C) whichspecifically binds to BCMA, wherein the third domain comprises an aminosequence set forth as any one of SEQ ID NOS: 346-460.

Provided herein in one embodiment is a B cell maturation agent (BCMA)binding trispecific protein comprising: (a) a first domain (A) whichspecifically binds to human CD3; (b) a second domain (B) which is ahalf-life extension domain; and (c) a third domain (C) whichspecifically binds to BCMA, wherein the third domain comprisescomplementarity determining regions CDR1, CDR2, and CDR3, wherein CDR1comprises an amino acid sequence set forth as any one of SEQ ID NOS:4-117, CDR2 comprises an amino acid sequence set forth as any one of SEQID NOS: 118-231, and CDR3 comprises an amino acid sequence set forth asany one of SEQ ID NOS: 232-345.

Provided herein is a pharmaceutical composition comprising a BCMAbinding trispecific protein as described herein and a pharmaceuticallyacceptable carrier.

Also provided herein is a process for the production of a BCMA bindingtrispecific protein described herein, said process comprising culturinga host transformed or transfected with a vector comprising a nucleicacid sequence encoding a BCMA binding trispecific protein underconditions allowing the expression of the BCMA binding trispecificprotein and recovering and purifying the produced protein from theculture.

One embodiment provides a method for the treatment or amelioration of atumorous disease, an autoimmune disease or an infection diseaseassociated with BCMA in a subject in need thereof, comprisingadministering to the subject a pharmaceutical composition comprising aBCMA binding trispecific protein, wherein the BCMA binding proteincomprises

(a) a first domain (A) which specifically binds to human CD3;(b) a second domain (B) which is a half-life extension domain; and(c) a third domain (C) which specifically binds to BCMA,wherein the domains are linked in the order H2N-(A)-(C)-(B)-COOH,H2N-(B)-(A)-(C)-COOH, H2N-(C)-(B)-(A)-COOH, H2N-(C)-(A)-(B)-COOH,H2N-(A)-(B)-(C)-COOH, H2N-(B)-(C)-(A)-COOH, wherein the domains arelinked by linkers L1 and L2.

Provided herein is a method for the treatment or amelioration of atumorous disease, an autoimmune disease or an infection diseaseassociated with BCMA in a subject in need thereof, comprisingadministering to the subject a pharmaceutical composition as describedherein.

A subject to be treated is, in some instances, a human.

In some instances, the method further comprises administration of one ormore additional agents in combination with the BCMA binding trispecificprotein.

The methods described herein are useful for treatment or amelioration ofa tumorous disease, wherein the BCMA binding trispecific proteinselectively binds to tumor cells expressing BCMA.

A tumorous disease to be treated with the described methods comprises aprimary cancer or a metastasis thereof. In one instance, the tumorousdisease comprises a B cell lineage cancer.

A B cell lineage cancer to be treated with the recited methods includes,but is not limited to, a multiple myeloma, a leukemia, a lymphoma, or ametastasis thereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 is schematic representation of an exemplary BCMA targetingtrispecific antigen-binding protein where the protein has an constantcore element comprising an anti-CD3ε single chain variable fragment(scFv) and an anti-ALB variable heavy chain region; and an anti-BCMAbinding domain that can be a VHH, a VH, scFv, a non-Ig binder, or aligand.

FIG. 2 illustrates the effect of exemplary BCMA targeting molecules(01H08, 01F07, 02F02, and BH253), containing an anti-BCMA bindingprotein according to the present disclosure, in killing of purifiedhuman T cells that expresses BCMA compared to a negative control.

FIG. 3 is an image of an SDS-PAGE of representative purified BCMAtrispecific molecules. Lane 1: 01F07-M34Y TriTAC™ non-reduced; Lane2:01F07-M34G-TriTAC™ non-reduced; Lane 3: 02B05 TriTAC™ non-reduced;Lane 4: 02G02-M34Y TriTAC™ non-reduced; Lane 5: 02G02 M34G TriTAC™non-reduced; Lane 6: Broad Range SDS-PAGE Standard (Bio-Rad #1610317);Lane 7: 01F07-M34Y TriTAC™ non-reduced; Lane 8:01F07-M34G-TriTAC™non-reduced; Lane 9: 02B05 TriTAC™ non-reduced; Lane 10: 02G02-M34YTriTAC™ non-reduced; Lane 11: 02G02 M34G TriTAC™ non-reduced; Lane 12:Broad Range SDS-PAGE Standard (Bio-Rad #1610317)

FIGS. 4A-4I illustrate the effect of exemplary BCMA trispecifictargeting molecules containing an anti-BCMA binding protein according tothe present disclosure in killing of Jeko1, MOLP-8 or OPM-2 cells thatexpress BCMA compared to a negative control.

FIGS. 5A-5D illustrate binding of an exemplary BCMA trispecifictargeting protein (02B05) to purified T Cells from four different humandonors, donor 02 (FIG. 5A), donor 35 (FIG. 5B), donor 81 (FIG. 5C),donor 86 (FIG. 5D).

FIGS. 6A-6F illustrate binding of an exemplary BCMA trispecifictargeting protein (02B05) to cells expressing BCMA, NCI-H929 (FIG. 6A),EJM (FIG. 6B), OPM2 (FIG. 6D), RPMI8226 (FIG. 6E); or cell lines lackingexpression of BCMA, NCI-H510A (FIG. 6C) and DMS-153 (FIG. 6F).

FIG. 7 illustrates the results of a TDCC assay using an exemplary BCMAtrispecific targeting protein (02B05) and BCMA expressing EJM cells, inpresence or absence of human serum albumin (HSA).

FIG. 8 illustrates the results of a TDCC assay using an exemplary BCMAtrispecific targeting protein (02B05) and BCMA expressing EJM cells,using a varying effector cells to target cells ratio.

FIG. 9 illustrates the results of a TDCC assay using an exemplary BCMAtrispecific targeting protein (02B05) and BCMA expressing OPM2 cells,using a varying effector cells to target cells ratio.

FIG. 10 illustrates the results of a TDCC assay using an exemplary BCMAtrispecific targeting protein (02B05) and BCMA expressing NCI-H929cells, using varying time-points and a 1:1 effector cells to targetcells ratio.

FIG. 11 illustrates the results of a TDCC assay using an exemplary BCMAtrispecific targeting protein (02B05), BCMA expressing EJM cells, and Tcells from four different donors, in presence of human serum albumin(HSA).

FIG. 12 illustrates the results of a TDCC assay using an exemplary BCMAtrispecific targeting protein (02B05), BCMA expressing NCI-H929 cells,and T cells from four different donors, in presence of human serumalbumin (HSA).

FIG. 13 illustrates the results of a TDCC assay using an exemplary BCMAtrispecific targeting protein (02B05), BCMA expressing OPM2 cells, and Tcells from four different donors, in presence of human serum albumin(HSA).

FIG. 14 illustrates the results of a TDCC assay using an exemplary BCMAtrispecific targeting protein (02B05), BCMA expressing RPMI8226 cells,and T cells from four different donors, in presence of human serumalbumin (HSA).

FIG. 15 illustrates the results of a TDCC assay using an exemplary BCMAtrispecific targeting protein (02B05), BCMA non-expressing OVCAR8 cells,and T cells from four different donors, in presence of human serumalbumin (HSA).

FIG. 16 illustrates the results of a TDCC assay using an exemplary BCMAtrispecific targeting protein (02B05), BCMA non-expressing NCI-H510Acells, and T cells from four different donors, in presence of humanserum albumin (HSA).

FIG. 17 illustrates the results of a TDCC assay using an exemplary BCMAtrispecific targeting protein (02B05), BCMA expressing NCI-H929 cells,and peripheral blood mononuclear cells (PBMC) from two differentcynomolgus donors, in presence of human serum albumin (HSA).

FIG. 18 illustrates the results of a TDCC assay using an exemplary BCMAtrispecific targeting protein (02B05), BCMA expressing RPMI8226 cells,and peripheral blood mononuclear cells (PBMC) from two differentcynomolgus donors, in presence of human serum albumin (HSA).

FIG. 19 illustrates the expression level of T cell activation biomarkerCD69, following a TDCC assay using an exemplary BCMA targetingtrispecific protein (02B05) and BCMA expressing cells EJM.

FIG. 20 illustrates the expression level of T cell activation biomarkerCD25, following a TDCC assay using an exemplary BCMA targetingtrispecific protein (02B05) and BCMA expressing cells EJM.

FIG. 21 illustrates the expression level of T cell activation biomarkerCD69, following a TDCC assay using an exemplary BCMA targetingtrispecific protein (02B05) and BCMA expressing cells OPM2.

FIG. 22 illustrates the expression level of T cell activation biomarkerCD25, following a TDCC assay using an exemplary BCMA targetingtrispecific protein (02B05) and BCMA expressing cells OPM2.

FIG. 23 illustrates the expression level of T cell activation biomarkerCD69, following a TDCC assay using an exemplary BCMA targetingtrispecific protein (02B05) and BCMA expressing cells RPMI8226.

FIG. 24 illustrates the expression level of T cell activation biomarkerCD25, following a TDCC assay using an exemplary BCMA targetingtrispecific protein (02B05) and BCMA expressing cells RPMI8226.

FIG. 25 illustrates the expression level of T cell activation biomarkerCD69, following a TDCC assay using an exemplary BCMA targetingtrispecific protein (02B05) and BCMA non-expressing cells OVCAR8.

FIG. 26 illustrates the expression level of T cell activation biomarkerCD25, following a TDCC assay using an exemplary BCMA targetingtrispecific protein (02B05) and BCMA non-expressing cells OVCAR8.

FIG. 27 illustrates the expression level of T cell activation biomarkerCD69, following a TDCC assay using an exemplary BCMA targetingtrispecific protein (02B05) and BCMA non-expressing cells NCI-H510A.

FIG. 28 illustrates the expression level of T cell activation biomarkerCD25, following a TDCC assay using an exemplary BCMA targetingtrispecific protein (02B05) and BCMA non-expressing cells NCI-H510A.

FIG. 29 illustrates the expression level a cytokine, TNF-α, inco-cultures of T cells and BCMA expressing target cells (EJM cells)treated with increasing concentrations of an exemplary BCMA targetingtrispecific (02B05) protein or with a negative control GFP trispecificprotein.

FIG. 30 illustrates tumor growth reduction in RPMI8226 xenograft model,treated with an exemplary BCMA targeting trispecific (02B05) protein, atvarying concentrations, or with a control vehicle.

FIG. 31 illustrates tumor growth reduction in Jeko1 xenograft model,treated with an exemplary BCMA targeting trispecific (02B05) protein, atvarying concentrations, or with a control vehicle.

FIG. 32 illustrates concentration of BCMA targeting trispecific proteinin serum samples from cynomolgus monkeys dosed with varyingconcentrations of an exemplary BCMA targeting trispecific (02B05)protein.

FIG. 33 the results of a TDCC assay using BCMA trispecific targetingprotein obtained from serum samples of cynomolgus monkeys collected 168hours after dosing with varying concentrations of an exemplary BCMAtargeting trispecific (02B05) protein, BCMA expressing EJM cells andpurified human T cells, in presence of serum from cynomolgus monkeysthat were not exposed to a BCMA targeting trispecific protein.

DETAILED DESCRIPTION OF THE INVENTION

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

Described herein are trispecific proteins that target B cell maturationantigen (BCMA), pharmaceutical compositions thereof (referred to hereinas BCMA binding trispecific protein, BCMA targeting trispecific protein,or BCMA trispecific antigen-binding protein) as well as nucleic acids,recombinant expression vectors and host cells for making such proteinsthereof. Also provided are methods of using the disclosed BCMA targetingtrispecific proteins in the prevention, and/or treatment of diseases,conditions and disorders. The BCMA targeting trispecific proteins arecapable of specifically binding to BCMA as well as CD3 and have ahalf-life extension domain, such as a domain binding to human albumin(ALB). FIG. 1 depicts a non-limiting example of a trispecificBCMA-binding protein.

An “antibody” typically refers to a Y-shaped tetrameric proteincomprising two heavy (H) and two light (L) polypeptide chains heldtogether by covalent disulfide bonds and non-covalent interactions.Human light chains comprise a variable domain (VL) and a constant domain(CL) wherein the constant domain may be readily classified as kappa orlambda based on amino acid sequence and gene loci. Each heavy chaincomprises one variable domain (VH) and a constant region, which in thecase of IgG, IgA, and IgD, comprises three domains termed CH1, CH2, andCH3 (IgM and IgE have a fourth domain, CH4). In IgG, IgA, and IgDclasses the CH1 and CH2 domains are separated by a flexible hingeregion, which is a proline and cysteine rich segment of variable length(generally from about 10 to about 60 amino acids in IgG). The variabledomains in both the light and heavy chains are joined to the constantdomains by a “J” region of about 12 or more amino acids and the heavychain also has a “D” region of about 10 additional amino acids. Eachclass of antibody further comprises inter-chain and intra-chaindisulfide bonds formed by paired cysteine residues. There are two typesof native disulfide bridges or bonds in immunoglobulin molecules:inter-chain and intra-chain disulfide bonds. The location and number ofinter-chain disulfide bonds vary according to the immunoglobulin classand species. Inter-chain disulfide bonds are located on the surface ofthe immunoglobulin, are accessible to solvent and are usually relativelyeasily reduced. In the human IgG1 isotype there are four inter-chaindisulfide bonds, one from each heavy chain to the light chain and twobetween the heavy chains. The inter-chain disulfide bonds are notrequired for chain association. As is well known the cysteine rich IgG1hinge region of the heavy chain has generally been held to consist ofthree parts: an upper hinge, a core hinge, and a lower hinge. Thoseskilled in the art will appreciate that the IgG1 hinge region containsthe cysteines in the heavy chain that comprise the inter-chain disulfidebonds (two heavy/heavy, two heavy/light), which provide structuralflexibility that facilitates Fab movements. The inter-chain disulfidebond between the light and heavy chain of IgG1 are formed between C214of the kappa or lambda light chain and C220 in the upper hinge region ofthe heavy chain. The inter-chain disulfide bonds between the heavychains are at positions C226 and C229 (all numbered per the EU indexaccording to Kabat, et al., infra.).

As used herein the term “antibody” includes polyclonal antibodies,multiclonal antibodies, monoclonal antibodies, chimeric antibodies,humanized and primatized antibodies, CDR grafted antibodies, humanantibodies, recombinantly produced antibodies, intrabodies,multispecific antibodies, bispecific antibodies, monovalent antibodies,multivalent antibodies, anti-idiotypic antibodies, synthetic antibodies,including muteins and variants thereof, immunospecific antibodyfragments such as Fd, Fab, F(ab′)2, F(ab′) fragments, single-chainfragments (e.g., ScFv and ScFvFc), disulfide-linked Fvs (sdFv), a Fdfragment consisting of the VH and CH1 domains, linear antibodies, singledomain antibodies such as sdAb (VH, VL, or VHH domains); and derivativesthereof including Fc fusions and other modifications, and any otherimmunoreactive molecule so long as it comprises a domain having abinding site for preferential association or binding with a BCMAprotein. Moreover, unless dictated otherwise by contextual constraintsthe term further comprises all classes of antibodies (i.e. IgA, IgD,IgE, IgG, and IgM) and all subclasses (i.e., IgG1, IgG2, IgG3, IgG4,IgA1, and IgA2). Heavy-chain constant domains that correspond to thedifferent classes of antibodies are typically denoted by thecorresponding lower case Greek letter alpha, delta, epsilon, gamma, andmu, respectively. Light chains of the antibodies from any vertebratespecies can be assigned to one of two clearly distinct types, calledkappa (kappa) and lambda (lambda), based on the amino acid sequences oftheir constant domains.

In some embodiments, the BCMA binding domain of the BCMA targetingtrispecific proteins of this disclosure comprise a heavy chain onlyantibody, such as a VH or a VHH domain. In some cases, the BCMA bindingproteins comprise a heavy chain only antibody that is an engineeredhuman VH domain. In some examples, the engineered human VH domain isproduced by panning of phage display libraries. In some embodiments, theBCMA binding domain of the BCMA targeting trispecific proteins of thisdisclosure comprise a VHH. The term “VHH,” as used herein, refers tosingle chain antibody binding domain devoid of light chain. In somecases, a VHH is derived from an antibody of the type that can be foundin Camelidae or cartilaginous fish which are naturally devoid of lightchains or to a synthetic and non-immunized VHH which can be constructedaccordingly. Each heavy chain comprises a variable region encoded by V-,D- and J exons. A VHH, in some cases, is a natural VHH, such as aCamelid-derived VHH, or a recombinant protein comprising a heavy chainvariable domain. In some embodiments, the VHH is derived from a speciesselected from the group consisting of camels, llamas, vicugnas,guanacos, and cartilaginous fish (such as, but not limited to, sharks).In another embodiment, the VHH is derived from an alpaca (such as, butnot limited to, a Huacaya Alpaca or a Suri alpaca).

As used herein, “Variable region” or “variable domain” refers to thefact that certain portions of the variable domains differ extensively insequence among antibodies and are used in the binding and specificity ofeach particular antibody for its particular antigen. However, thevariability is not evenly distributed throughout the variable domains ofantibodies. It is concentrated in three segments calledcomplementarity-determining regions (CDRs) or hypervariable regions bothin the light-chain (VL) and the heavy-chain (VH) variable domains. Themore highly conserved portions of variable domains are called theframework (FR). The variable domains of native heavy and light chainseach comprise four FR regions, largely adopting a β-sheet configuration,connected by three CDRs, which form loops connecting, and in some casesforming part of, the β sheet structure. The CDRs in each chain are heldtogether in close proximity by the FR regions and, with the CDRs fromthe other chain, contribute to the formation of the antigen-binding siteof antibodies (see Kabat et al., Sequences of Proteins of ImmunologicalInterest, Fifth Edition, National Institute of Health, Bethesda, Md.(1991)). The constant domains are not involved directly in binding anantibody to an antigen, but exhibit various effector functions, such asparticipation of the antibody in antibody-dependent cellular toxicity.ScFv fragments (or single chain fragment variable), which in some casesare obtained by genetic engineering, associate in a single polypeptidechain, the VH and the VL region of an antibody, separated by a peptidelinker.

In some embodiments of this disclosure, the BCMA binding domain of theBCMA targeting trispecific proteins comprise heavy chain onlyantibodies, such as VH or VHH domains, and comprise three CDRs. Suchheavy chain only antibodies, in some embodiments, bind BCMA as a monomerwith no dependency on dimerization with a VL (light chain variable)region for optimal binding affinity. In some embodiments of thisdisclosure, the CD3 binding domain of the BCMA targeting trispecificproteins comprises a scFv. In some embodiments of this disclosure, thealbumin binding domain of the BCMA targeting trispecific proteinscomprise a heavy chain only antibody, such as a single domain antibodycomprising a VH domain or a VHH domain.

The assignment of amino acids to each domain, framework region and CDRis, in some embodiments, in accordance with one of the numbering schemesprovided by Kabat et al. (1991) Sequences of Proteins of ImmunologicalInterest (5th Ed.), US Dept. of Health and Human Services, PHS, NIH, NIHPublication no. 91-3242; Chothia et al., 1987, PMID: 3681981; Chothia etal., 1989, PMID: 2687698; MacCallum et al., 1996, PMID: 8876650; orDubel, Ed. (2007) Handbook of Therapeutic Antibodies, 3rd Ed., Wily-VCHVerlag GmbH and Co or AbM (Oxford Molecular/MSI Pharmacopia) unlessotherwise noted. It is not intended that CDRs of the present disclosurenecessarily correspond to the Kabat numbering convention.

The term “Framework” or “FR” residues (or regions) refer to variabledomain residues other than the CDR or hypervariable region residues asherein defined. A “human consensus framework” is a framework whichrepresents the most commonly occurring amino acid residue in a selectionof human immunoglobulin VL or VH framework sequences.

As used herein, the term “Percent (%) amino acid sequence identity” withrespect to a sequence is defined as the percentage of amino acidresidues in a candidate sequence that are identical with the amino acidresidues in the specific sequence, after aligning the sequences andintroducing gaps, if necessary, to achieve the maximum percent sequenceidentity, and not considering any conservative substitutions as part ofthe sequence identity. Alignment for purposes of determining percentamino acid sequence identity can be achieved in various ways that arewithin the skill in the art, for instance, using publicly availablecomputer software such as EMBOSS MATCHER, EMBOSS WATER, EMBOSSSTRETCHER, EMBOSS NEEDLE, EMBOSS LALIGN, BLAST, BLAST-2, ALIGN orMegalign (DNASTAR) software. Those skilled in the art can determineappropriate parameters for measuring alignment, including any algorithmsneeded to achieve maximal alignment over the full length of thesequences being compared.

As used herein, “elimination half-time” is used in its ordinary sense,as is described in Goodman and Gillman's The Pharmaceutical Basis ofTherapeutics 21-25 (Alfred Goodman Gilman, Louis S. Goodman, and AlfredGilman, eds., 6th ed. 1980). Briefly, the term is meant to encompass aquantitative measure of the time course of drug elimination. Theelimination of most drugs is exponential (i.e., follows first-orderkinetics), since drug concentrations usually do not approach thoserequired for saturation of the elimination process. The rate of anexponential process may be expressed by its rate constant, k, whichexpresses the fractional change per unit of time, or by its half-time,t1/2 the time required for 50% completion of the process. The units ofthese two constants are time-1 and time, respectively. A first-orderrate constant and the half-time of the reaction are simply related(k×t1/2=0.693) and may be interchanged accordingly. Since first-orderelimination kinetics dictates that a constant fraction of drug is lostper unit time, a plot of the log of drug concentration versus time islinear at all times following the initial distribution phase (i.e. afterdrug absorption and distribution are complete). The half-time for drugelimination can be accurately determined from such a graph.

As used herein, the term “binding affinity” refers to the affinity ofthe proteins described in the disclosure to their binding targets, andis expressed numerically using “Kd” values. If two or more proteins areindicated to have comparable binding affinities towards their bindingtargets, then the Kd values for binding of the respective proteinstowards their binding targets, are within ±2-fold of each other. If twoor more proteins are indicated to have comparable binding affinitiestowards single binding target, then the Kd values for binding of therespective proteins towards said single binding target, are within±2-fold of each other. If a protein is indicated to bind two or moretargets with comparable binding affinities, then the Kd values forbinding of said protein to the two or more targets are within ±2-fold ofeach other. In general, a higher Kd value corresponds to a weakerbinding. In some embodiments, the “Kd” is measured by a radiolabeledantigen binding assay (MA) or surface plasmon resonance assays using aBIAcore™-2000 or a BIAcore™-3000 (BIAcore, Inc., Piscataway, N.J.). Incertain embodiments, an “on-rate” or “rate of association” or“association rate” or “kon” and an “off-rate” or “rate of dissociation”or “dissociation rate” or “koff” are also determined with the surfaceplasmon resonance technique using a BIAcore™-2000 or a BIAcore™-3000(BIAcore, Inc., Piscataway, N.J.). In additional embodiments, the “Kd”,“kon”, and “koff” are measured using the OCTET® Systems (Pall LifeSciences). In an exemplary method for measuring binding affinity usingthe OCTET® Systems, the ligand, e.g., biotinylated human or cynomolgusBCMA, is immobilized on the OCTET® streptavidin capillary sensor tipsurface which streptavidin tips are then activated according tomanufacturer's instructions using about 20-50 μg/ml human or cynomolgusBCMA protein. A solution of PBS/Casein is also introduced as a blockingagent. For association kinetic measurements, BCMA binding proteinvariants are introduced at a concentration ranging from about 10 ng/mLto about 100 μg/mL, about 50 ng/mL to about 5 μg/mL, or about 2 ng/mL toabout 20 μg/mL. In some embodiments, the BCMA binding single domainproteins are used at a concentration ranging from about 2 ng/mL to about20 μg/mL. Complete dissociation is observed in case of the negativecontrol, assay buffer without the binding proteins. The kineticparameters of the binding reactions are then determined using anappropriate tool, e.g., ForteBio software.

The term “about” or “approximately” means within an acceptable errorrange for the particular value as determined by one of ordinary skill inthe art, which will depend in part on how the value is measured ordetermined, e.g., the limitations of the measurement system. Forexample, “about” can mean within 1 or more than 1 standard deviation,per the practice in the given value. Where particular values aredescribed in the application and claims, unless otherwise stated theterm “about” should be assumed to mean an acceptable error range for theparticular value.

The terms “individual,” “patient,” or “subject” are usedinterchangeably. None of the terms require or are limited to situationscharacterized by the supervision (e.g. constant or intermittent) of ahealth care worker (e.g. a doctor, a registered nurse, a nursepractitioner, a physician's assistant, an orderly, or a hospice worker).

The terminology used herein is for the purpose of describing particularcases only and is not intended to be limiting. As used herein, thesingular forms “a,” “an” and “the” are intended to include the pluralforms as well, unless the context clearly indicates otherwise.Furthermore, to the extent that the terms “including”, “includes”,“having”, “has”, “with”, or variants thereof are used in either thedetailed description and/or the claims, such terms are intended to beinclusive in a manner similar to the term “comprising.”

In one aspect, the BCMA targeting trispecific proteins comprise a domain(A) which specifically binds to CD3, a domain (B) which specificallybinds to human albumin (ALB), and a domain (C) which specifically bindsto BCMA. The three domains in BCMA targeting trispecific proteins arearranged in any order. Thus, it is contemplated that the domain order ofthe BCMA targeting trispecific proteins are:

-   -   H₂N-(A)-(B)-(C)-COOH,    -   H₂N-(A)-(C)-(B)-COOH,    -   H₂N-(B)-(A)-(C)-COOH,    -   H₂N-(B)-(C)-(A)-COOH,    -   H₂N-(C)-(B)-(A)-COOH, or    -   H₂N-(C)-(A)-(B)-COOH.

In some embodiments, the BCMA targeting trispecific proteins have adomain order of H₂N-(A)-(B)-(C)-COOH. In some embodiments, the BCMAtargeting trispecific proteins have a domain order ofH₂N-(A)-(C)-(B)-COOH. In some embodiments, the BCMA targetingtrispecific proteins have a domain order of H₂N-(B)-(A)-(C)-COOH. Insome embodiments, the BCMA targeting trispecific proteins have a domainorder of H₂N-(B)-(C)-(A)-COOH. In some embodiments, the BCMA targetingtrispecific proteins have a domain order of H₂N-(C)-(B)-(A)-COOH. Insome embodiments, the BCMA targeting trispecific proteins have a domainorder of H₂N-(C)-(A)-(B)-COOH. In some embodiments, the anti-BCMA domain(the anti-target domain, T), the anti-CD3 domain (C), and the anti-ALBdomain (A) are in an anti-CD3: anti-ALB: anti-BCMA (CAT) orientation. Insome embodiments, the anti-BCMA domain (the anti-target domain, T) theanti-CD3 domain (C), and the anti-ALB domain (A) are in an anti-BCMA:anti-ALB: anti-CD3 (TAC) orientation.

In some embodiments, the BCMA targeting trispecific proteins have theHSA binding domain as the middle domain, such that the domain order isH₂N-(A)-(B)-(C)-COOH or H₂N-(C)-(B)-(A)-COOH. It is contemplated that insuch embodiments where the ALB binding domain as the middle domain, theCD3 and BCMA binding domains are afforded additional flexibility to bindto their respective targets.

In some embodiments, the BCMA targeting trispecific proteins describedherein comprise a polypeptide having a sequence described in theSequence Table (SEQ ID NO: 483-597) and subsequences thereof. In someembodiments, the trispecific antigen binding protein comprises apolypeptide having at least 70%-95% or more homology to a sequencedescribed in the Sequence Table (SEQ ID NO: 483-597). In someembodiments, the trispecific antigen binding protein comprises apolypeptide having at least 70%, 75%, 80%, 85%, 90%, 95%, or morehomology to a sequence described in the Sequence Table 1 (SEQ ID NO:483-597).

The BCMA targeting trispecific proteins described herein are designed toallow specific targeting of cells expressing BCMA by recruitingcytotoxic T cells. This improves efficacy compared to ADCC (antibodydependent cell-mediated cytotoxicity), which is using full lengthantibodies directed to a sole antigen and is not capable of directlyrecruiting cytotoxic T cells. In contrast, by engaging CD3 moleculesexpressed specifically on these cells, the BCMA targeting trispecificproteins can crosslink cytotoxic T cells with cells expressing BCMA in ahighly specific fashion, thereby directing the cytotoxic potential ofthe T cell towards the target cell. The BCMA targeting trispecificproteins described herein engage cytotoxic T cells via binding to thesurface-expressed CD3 proteins, which form part of the TCR. Simultaneousbinding of several BCMA trispecific antigen-binding protein to CD3 andto BCMA expressed on the surface of particular cells causes T cellactivation and mediates the subsequent lysis of the particular BCMAexpressing cell. Thus, BCMA targeting trispecific proteins arecontemplated to display strong, specific and efficient target cellkilling. In some embodiments, the BCMA targeting trispecific proteinsdescribed herein stimulate target cell killing by cytotoxic T cells toeliminate pathogenic cells (e.g., tumor cells expressing BCMA). In someof such embodiments, cells are eliminated selectively, thereby reducingthe potential for toxic side effects.

The BCMA targeting trispecific proteins described herein confer furthertherapeutic advantages over traditional monoclonal antibodies and othersmaller bispecific molecules. Generally, the effectiveness ofrecombinant protein pharmaceuticals depends heavily on the intrinsicpharmacokinetics of the protein itself. One such benefit here is thatthe BCMA targeting trispecific proteins described herein have extendedpharmacokinetic elimination half-time due to having a half-lifeextension domain such as a domain specific to HSA. In this respect, theBCMA targeting trispecific proteins described herein have an extendedserum elimination half-time of about two, three, about five, aboutseven, about 10, about 12, or about 14 days in some embodiments. Thiscontrasts to other binding proteins such as BiTE or DART molecules whichhave relatively much shorter elimination half-times. For example, theBiTE CD19×CD3 bispecific scFv-scFv fusion molecule requires continuousintravenous infusion (i.v.) drug delivery due to its short eliminationhalf-time. The longer intrinsic half-times of the BCMA targetingtrispecific proteins solve this issue thereby allowing for increasedtherapeutic potential such as low-dose pharmaceutical formulations,decreased periodic administration and/or novel pharmaceuticalcompositions.

The BCMA targeting trispecific proteins described herein also have anoptimal size for enhanced tissue penetration and tissue distribution.Larger sizes limit or prevent penetration or distribution of the proteinin the target tissues. The BCMA targeting trispecific proteins describedherein avoid this by having a small size that allows enhanced tissuepenetration and distribution. Accordingly, the BCMA targetingtrispecific proteins described herein, in some embodiments have a sizeof about 50 kD to about 80 kD, about 50 kD to about 75 kD, about 50 kDto about 70 kD, or about 50 kD to about 65 kD. Thus, the size of theBCMA targeting trispecific proteins is advantageous over IgG antibodieswhich are about 150 kD and the BiTE and DART diabody molecules which areabout 55 kD but are not half-life extended and therefore cleared quicklythrough the kidney.

In further embodiments, the BCMA targeting trispecific proteinsdescribed herein have an optimal size for enhanced tissue penetrationand distribution. In these embodiments, the BCMA targeting trispecificproteins are constructed to be as small as possible, while retainingspecificity toward its targets. Accordingly, in these embodiments, theBCMA targeting trispecific proteins described herein have a size ofabout 20 kD to about 40 kD or about 25 kD to about 35 kD to about 40 kD,to about 45 kD, to about 50 kD, to about 55 kD, to about 60 kD, to about65 kD. In some embodiments, the BCMA targeting trispecific proteinsdescribed herein have a size of about 50 kD, 49, kD, 48 kD, 47 kD, 46kD, 45 kD, 44 kD, 43 kD, 42 kD, 41 kD, 40 kD, about 39 kD, about 38 kD,about 37 kD, about 36 kD, about 35 kD, about 34 kD, about 33 kD, about32 kD, about 31 kD, about 30 kD, about 29 kD, about 28 kD, about 27 kD,about 26 kD, about 25 kD, about 24 kD, about 23 kD, about 22 kD, about21 kD, or about 20 kD. An exemplary approach to the small size isthrough the use of single domain antibody (sdAb) fragments for each ofthe domains. For example, a particular BCMA trispecific antigen-bindingprotein has an anti-CD3 sdAb, anti-ALB sdAb and an sdAb for BCMA. Thisreduces the size of the exemplary BCMA trispecific antigen-bindingprotein to under 40 kD. Thus in some embodiments, the domains of theBCMA targeting trispecific proteins are all single domain antibody(sdAb) fragments. In other embodiments, the BCMA targeting trispecificproteins described herein comprise small molecule entity (SME) bindersfor ALB and/or the BCMA. SME binders are small molecules averaging about500 to 2000 Da in size and are attached to the BCMA targetingtrispecific proteins by known methods, such as sortase ligation orconjugation. In these instances, one of the domains of BCMA trispecificantigen-binding protein is a sortase recognition sequence, e.g., LPETG(SEQ ID NO: 482). To attach a SME binder to BCMA trispecificantigen-binding protein with a sortase recognition sequence, the proteinis incubated with a sortase and a SME binder whereby the sortaseattaches the SME binder to the recognition sequence. Known SME bindersinclude MIP-1072 and MIP-1095 which bind to BCMA.

In yet other embodiments, the domain which binds to BCMA of BCMAtargeting trispecific proteins described herein comprise a knottinpeptide for binding BCMA. Knottins are disulfide-stabilized peptideswith a cysteine knot scaffold and have average sizes about 3.5 kD.Knottins have been contemplated for binding to certain tumor moleculessuch as BCMA. In further embodiments, domain which binds to BCMA of BCMAtargeting trispecific proteins described herein comprise a natural BCMAligand.

Another feature of the BCMA targeting trispecific proteins describedherein is that they are of a single-polypeptide design with flexiblelinkage of their domains. This allows for facile production andmanufacturing of the BCMA targeting trispecific proteins as they can beencoded by single cDNA molecule to be easily incorporated into a vector.Further, because the BCMA targeting trispecific proteins describedherein are a monomeric single polypeptide chain, there are no chainpairing issues or a requirement for dimerization. It is contemplatedthat the BCMA targeting trispecific proteins described herein have areduced tendency to aggregate unlike other reported molecules such asbispecific proteins with Fc-gamma immunoglobulin domains.

In the BCMA targeting trispecific proteins described herein, the domainsare linked by internal linkers L1 and L2, where L1 links the first andsecond domain of the BCMA targeting trispecific proteins and L2 linksthe second and third domains of the BCMA targeting trispecific proteins.Linkers L1 and L2 have an optimized length and/or amino acidcomposition. In some embodiments, linkers L1 and L2 are the same lengthand amino acid composition. In other embodiments, L1 and L2 aredifferent. In certain embodiments, internal linkers L1 and/or L2 are“short”, i.e., consist of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12amino acid residues. Thus, in certain instances, the internal linkersconsist of about 12 or less amino acid residues. In the case of 0 aminoacid residues, the internal linker is a peptide bond. In certainembodiments, internal linkers L1 and/or L2 are “long”, i.e., “consistof” 15, 20 or 25 amino acid residues. In some embodiments, theseinternal linkers consist of about 3 to about 15, for example 8, 9 or 10contiguous amino acid residues. Regarding the amino acid composition ofthe internal linkers L1 and L2, peptides are selected with propertiesthat confer flexibility to the BCMA targeting trispecific proteins, donot interfere with the binding domains as well as resist cleavage fromproteases. For example, glycine and serine residues generally provideprotease resistance. Examples of internal linkers suitable for linkingthe domains in the BCMA targeting trispecific proteins include but arenot limited to (GS)_(n) (SEQ ID NO: 472), (GGS)_(n) (SEQ ID NO: 473),(GGGS)_(n) (SEQ ID NO: 474), (GGSG)_(n) (SEQ ID NO: 475), (GGSGG)_(n)(SEQ ID NO: 476), (GGGGS)_(n) (SEQ ID NO: 477), (GGGGG)_(n) (SEQ ID NO:478), or (GGG)_(n) (SEQ ID NO: 479), wherein n is 1, 2, 3, 4, 5, 6, 7,8, 9, or 10. In one embodiment, internal linker L1 and/or L2 is (GGGGS)4(SEQ ID NO: 480) or (GGGGS)3 (SEQ ID NO: 481).

CD3 Binding Domain

The specificity of the response of T cells is mediated by therecognition of an antigen (displayed in context of a majorhistocompatibility complex, WIC) by the TCR. As part of the TCR, CD3 isa protein complex that includes a CD3γ (gamma) chain, a CD3δ (delta)chain, and two CD3ε (epsilon) chains which are present on the cellsurface. CD3 associates with the α (alpha) and β (beta) chains of theTCR as well as CD3 ζ (zeta) altogether to comprise the complete TCR.Clustering of CD3 on T cells, such as by immobilized anti-CD3 antibodiesleads to T cell activation similar to the engagement of the T cellreceptor but independent of its clone-typical specificity.

In one aspect, the BCMA targeting trispecific proteins described hereincomprise a domain which specifically binds to CD3. In one aspect, theBCMA targeting trispecific proteins described herein comprise a domainwhich specifically binds to human CD3. In some embodiments, the BCMAtargeting trispecific proteins described herein comprise a domain whichspecifically binds to CD3γ. In some embodiments, the BCMA targetingtrispecific proteins described herein comprise a domain whichspecifically binds to CD3δ. In some embodiments, the BCMA targetingtrispecific proteins described herein comprise a domain whichspecifically binds to CD3ε.

In further embodiments, the BCMA targeting trispecific proteinsdescribed herein comprise a domain which specifically binds to the TCR.In certain instances, the BCMA targeting trispecific proteins describedherein comprise a domain which specifically binds the a chain of theTCR. In certain instances, the BCMA targeting trispecific proteinsdescribed herein comprise a domain which specifically binds the β chainof the TCR.

In some embodiments, the CD3 binding domain of the BCMA trispecificantigen-binding protein can be any domain that binds to CD3 includingbut not limited to domains from a monoclonal antibody, a polyclonalantibody, a recombinant antibody, a human antibody, a humanizedantibody. In some instances, it is beneficial for the CD3 binding domainto be derived from the same species in which the BCMA trispecificantigen-binding protein will ultimately be used in. For example, for usein humans, it may be beneficial for the CD3 binding domain of the BCMAtrispecific antigen-binding protein to comprise human or humanizedresidues from the antigen binding domain of an antibody or antibodyfragment.

Thus, in one aspect, the antigen-binding domain comprises a humanized orhuman antibody or an antibody fragment, or a murine antibody or antibodyfragment. In one embodiment, the humanized or human anti-CD3 bindingdomain comprises one or more (e.g., all three) light chain complementarydetermining region 1 (LC CDR1), light chain complementary determiningregion 2 (LC CDR2), and light chain complementary determining region 3(LC CDR3) of a humanized or human anti-CD3 binding domain describedherein, and/or one or more (e.g., all three) heavy chain complementarydetermining region 1 (HC CDR1), heavy chain complementary determiningregion 2 (HC CDR2), and heavy chain complementary determining region 3(HC CDR3) of a humanized or human anti-CD3 binding domain describedherein, e.g., a humanized or human anti-CD3 binding domain comprisingone or more, e.g., all three, LC CDRs and one or more, e.g., all three,HC CDRs.

In some embodiments, the humanized or human anti-CD3 binding domaincomprises a humanized or human light chain variable region specific toCD3 where the light chain variable region specific to CD3 compriseshuman or non-human light chain CDRs in a human light chain frameworkregion. In certain instances, the light chain framework region is a λ(lambda) light chain framework. In other instances, the light chainframework region is a κ (kappa) light chain framework.

In some embodiments, the humanized or human anti-CD3 binding domaincomprises a humanized or human heavy chain variable region specific toCD3 where the heavy chain variable region specific to CD3 compriseshuman or non-human heavy chain CDRs in a human heavy chain frameworkregion.

In certain instances, the complementary determining regions of the heavychain and/or the light chain are derived from known anti-CD3 antibodies,such as, for example, muromonab-CD3 (OKT3), otelixizumab (TRX4),teplizumab (MGA031), visilizumab (Nuvion), SP34, TR-66 or X35-3, VIT3,BMA030 (BW264/56), CLB-T3/3, CRIS7, YTH12.5, F111-409, CLB-T3.4.2,TR-66, WT32, SPv-T3b, 11D8, XIII-141, XIII-46, XIII-87, 12F6,T3/RW2-8C8, T3/RW2-4B6, OKT3D, M-T301, SMC2, F101.01, UCHT-1 and WT-31.

In one embodiment, the anti-CD3 binding domain is a single chainvariable fragment (scFv) comprising a light chain and a heavy chain ofan amino acid sequence provided herein. As used herein, “single chainvariable fragment” or “scFv” refers to an antibody fragment comprising avariable region of a light chain and at least one antibody fragmentcomprising a variable region of a heavy chain, wherein the light andheavy chain variable regions are contiguously linked via a shortflexible polypeptide linker, and capable of being expressed as a singlepolypeptide chain, and wherein the scFv retains the specificity of theintact antibody from which it is derived. In an embodiment, the anti-CD3binding domain comprises: a light chain variable region comprising anamino acid sequence having at least one, two or three modifications(e.g., substitutions) but not more than 30, 20 or 10 modifications(e.g., substitutions) of an amino acid sequence of a light chainvariable region provided herein, or a sequence with 95-99% identity withan amino acid sequence provided herein; and/or a heavy chain variableregion comprising an amino acid sequence having at least one, two orthree modifications (e.g., substitutions) but not more than 30, 20 or 10modifications (e.g., substitutions) of an amino acid sequence of a heavychain variable region provided herein, or a sequence with 95-99%identity to an amino acid sequence provided herein. In one embodiment,the humanized or human anti-CD3 binding domain is a scFv, and a lightchain variable region comprising an amino acid sequence describedherein, is attached to a heavy chain variable region comprising an aminoacid sequence described herein, via a scFv linker. The light chainvariable region and heavy chain variable region of a scFv can be, e.g.,in any of the following orientations: light chain variable region-scFvlinker-heavy chain variable region or heavy chain variable region-scFvlinker-light chain variable region.

In some instances, scFvs which bind to CD3 are prepared according toknown methods. For example, scFv molecules can be produced by linking VHand VL regions together using flexible polypeptide linkers. The scFvmolecules comprise a scFv linker (e.g., a Ser-Gly linker) with anoptimized length and/or amino acid composition. Accordingly, in someembodiments, the length of the scFv linker is such that the VH or VLdomain can associate intermolecularly with the other variable domain toform the CD3 binding site. In certain embodiments, such scFv linkers are“short”, i.e. consist of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12amino acid residues. Thus, in certain instances, the scFv linkersconsist of about 12 or less amino acid residues. In the case of 0 aminoacid residues, the scFv linker is a peptide bond. In some embodiments,these scFv linkers consist of about 3 to about 15, for example 8, 9 or10 contiguous amino acid residues. Regarding the amino acid compositionof the scFv linkers, peptides are selected that confer flexibility, donot interfere with the variable domains as well as allow inter-chainfolding to bring the two variable domains together to form a functionalCD3 binding site. For example, scFv linkers comprising glycine andserine residues generally provide protease resistance. In someembodiments, linkers in a scFv comprise glycine and serine residues. Theamino acid sequence of the scFv linkers can be optimized, for example,by phage-display methods to improve the CD3 binding and production yieldof the scFv. Examples of peptide scFv linkers suitable for linking avariable light domain and a variable heavy domain in a scFv include butare not limited to (GS)_(n) (SEQ ID NO: 472), (GGS)_(n) (SEQ ID NO:473), (GGGS)_(n) (SEQ ID NO: 474), (GGSG)_(n) (SEQ ID NO: 475),(GGSGG)_(n) (SEQ ID NO: 476), (GGGGS)_(n) (SEQ ID NO: 477), (GGGGG)_(n)(SEQ ID NO: 478), or (GGG)_(n)(SEQ ID NO: 479), wherein n is 1, 2, 3, 4,5, 6, 7, 8, 9, or 10. In one embodiment, internal linker L1 and/or L2 is(GGGGS)₄ (SEQ ID NO: 480) or (GGGGS)₃ (SEQ ID NO: 481). Variation in thelinker length may retain or enhance activity, giving rise to superiorefficacy in activity studies.

In some embodiments, CD3 binding domain of BCMA trispecificantigen-binding protein has an affinity to CD3 on CD3 expressing cellswith a K_(D) of 1000 nM or less, 500 nM or less, 200 nM or less, 100 nMor less, 80 nM or less, 50 nM or less, 20 nM or less, 10 nM or less, 5nM or less, 1 nM or less, or 0.5 nM or less. In some embodiments, theCD3 binding domain of BCMA trispecific antigen-binding protein has anaffinity to CD3ε, γ, or δ with a K_(D) of 1000 nM or less, 500 nM orless, 200 nM or less, 100 nM or less, 80 nM or less, 50 nM or less, 20nM or less, 10 nM or less, 5 nM or less, 1 nM or less, or 0.5 nM orless. In further embodiments, CD3 binding domain of BCMA trispecificantigen-binding protein has low affinity to CD3, i.e., about 100 nM orgreater.

The affinity to bind to CD3 can be determined, for example, by theability of the BCMA trispecific antigen-binding protein itself or itsCD3 binding domain to bind to CD3 coated on an assay plate; displayed ona microbial cell surface; in solution; etc. The binding activity of theBCMA trispecific antigen-binding protein itself or its CD3 bindingdomain of the present disclosure to CD3 can be assayed by immobilizingthe ligand (e.g., CD3) or the BCMA trispecific antigen-binding proteinitself or its CD3 binding domain, to a bead, substrate, cell, etc.Agents can be added in an appropriate buffer and the binding partnersincubated for a period of time at a given temperature. After washes toremove unbound material, the bound protein can be released with, forexample, SDS, buffers with a high pH, and the like and analyzed, forexample, by Surface Plasmon Resonance (SPR).

Half-Life Extension Domain

Contemplated herein are domains which extend the half-life of anantigen-binding domain. Such domains are contemplated to include but arenot limited to Albumin binding domains, Fc domains, small molecules, andother half-life extension domains known in the art.

Human albumin (ALB) (molecular mass of about 67 kDa) is the mostabundant protein in plasma, present at about 50 mg/ml (600 μM), and hasa half-life of around 20 days in humans. ALB serves to maintain plasmapH, contributes to colloidal blood pressure, functions as carrier ofmany metabolites and fatty acids, and serves as a major drug transportprotein in plasma.

Noncovalent association with albumin extends the elimination half-timeof short lived proteins. For example, a recombinant fusion of an albuminbinding domain to a Fab fragment resulted in an in vivo clearance of 25-and 58-fold and a half-life extension of 26- and 37-fold whenadministered intravenously to mice and rabbits respectively as comparedto the administration of the Fab fragment alone. In another example,when insulin is acylated with fatty acids to promote association withalbumin, a protracted effect was observed when injected subcutaneouslyin rabbits or pigs. Together, these studies demonstrate a linkagebetween albumin binding and prolonged action.

In one aspect, the BCMA targeting trispecific proteins described hereincomprise a half-life extension domain, for example a domain whichspecifically binds to ALB. In some embodiments, the ALB binding domainof BCMA trispecific antigen-binding protein can be any domain that bindsto ALB including but not limited to domains from a monoclonal antibody,a polyclonal antibody, a recombinant antibody, a human antibody, ahumanized antibody. In some embodiments, the ALB binding domain is asingle chain variable fragments (scFv), single-domain antibody such as aheavy chain variable domain (VH), a light chain variable domain (VL) anda variable domain (VHH) of camelid derived single domain antibody,peptide, ligand or small molecule entity specific for HSA. In certainembodiments, the ALB binding domain is a single-domain antibody. Inother embodiments, the HSA binding domain is a peptide. In furtherembodiments, the HSA binding domain is a small molecule. It iscontemplated that the HSA binding domain of BCMA trispecificantigen-binding protein is fairly small and no more than 25 kD, no morethan 20 kD, no more than 15 kD, or no more than 10 kD in someembodiments. In certain instances, the ALB binding is 5 kD or less if itis a peptide or small molecule entity.

The half-life extension domain of BCMA trispecific antigen-bindingprotein provides for altered pharmacodynamics and pharmacokinetics ofthe BCMA trispecific antigen-binding protein itself. As above, thehalf-life extension domain extends the elimination half-time. Thehalf-life extension domain also alters pharmacodynamic propertiesincluding alteration of tissue distribution, penetration, and diffusionof the trispecific antigen-binding protein. In some embodiments, thehalf-life extension domain provides for improved tissue (includingtumor) targeting, tissue distribution, tissue penetration, diffusionwithin the tissue, and enhanced efficacy as compared with a proteinwithout a half-life extension domain. In one embodiment, therapeuticmethods effectively and efficiently utilize a reduced amount of thetrispecific antigen-binding protein, resulting in reduced side effects,such as reduced non-tumor cell cytotoxicity.

Further, the binding affinity of the half-life extension domain can beselected so as to target a specific elimination half-time in aparticular trispecific antigen-binding protein. Thus, in someembodiments, the half-life extension domain has a high binding affinity.In other embodiments, the half-life extension domain has a mediumbinding affinity. In yet other embodiments, the half-life extensiondomain has a low or marginal binding affinity. Exemplary bindingaffinities include KD concentrations at 10 nM or less (high), between 10nM and 100 nM (medium), and greater than 100 nM (low). As above, bindingaffinities to ALB are determined by known methods such as SurfacePlasmon Resonance (SPR).

In some embodiments, ALB binding domains described herein comprise asingle domain antibody.

B Cell Maturation Antigen (BCMA) Binding Domain

B cell maturation antigen (BCMA, TNFRSF17, CD269) is a transmembraneprotein belonging to the tumor necrosis family receptor (TNFR) superfamily that is primarily expressed on terminally differentiated B cells.BCMA expression is restricted to the B cell lineage and mainly presenton plasma cells and plasmablasts and to some extent on memory B cells,but virtually absent on peripheral and naive B cells. BCMA is alsoexpressed on multiple myeloma (MM) cells, on leukemia cells and lymphomacells.

BCMA was identified through molecular analysis of a t(4;16)(q26;p13)translocation found in a human intestinal T cell lymphoma and anin-frame sequence was mapped to the 16p13.1 chromosome band.

Human BCMA cDNA has an open reading frame of 552 bp that encodes a 184amino acid polypeptide. The BCMA gene is organized into three exons thatare separated by two introns, each flanked by GT donor and AG acceptorconsensus splicing sites, and codes for a transcript of 1.2 kb. Thestructure of BCMA protein includes an integral transmembrane proteinbased on a central 24 amino acid hydrophobic region in an alpha-helixstructure.

The murine BCMA gene is located on chromosome 16 syntenic to the human16p13 region, and also includes three exons that are separated by twointrons. The gene encodes a 185 amino acid protein. Murine BCMA mRNA isexpressed as a 404 bp transcript at the highest levels in plasmacytomacells (J558) and at modest levels in the A20 B cell lymphoma line.Murine BCMA mRNA transcripts have also been detected at low levels in Tcell lymphoma (EL4, BW5147) and dendritic cell (CB1D6, D2SC1) lines incontrast to human cell lines of T cell and dendritic cell origin. Themurine BCMA cDNA sequence has 69.3% nucleotide identity with the humanBCMA cDNA sequence and slightly higher identity (73.7%) when comparingthe coding regions between these two cDNA sequences. Mouse BCMA proteinis 62% identical to human BCMA protein and, like human BCMA, contains asingle hydrophobic region, which may be an internal transmembranesegment. The N-terminal 40 amino acid domain of both murine and humanBCMA protein have six conserved cysteine residues, consistent with theformation of a cysteine repeat motif found in the extracellular domainof TNFRs. Similar to members of the TNFR superfamily, BCMA proteincontains a conserved aromatic residue four to six residues C-terminalfrom the first cysteine.

BCMA is not expressed at the cell surface, but rather, is located on theGolgi apparatus. The amount of BCMA expression is proportional to thestage of cellular differentiation (highest in plasma cells).

It is involved in B cell development and homeostasis due to itsinteraction with its ligands BAFF (B cell activating factor, alsodesignated as TALL-1 or TNFSF13B) and APRIL (A proliferation inducingligand).

BCMA regulates different aspects of humoral immunity, B cell developmentand homeostasis along with its family members TACI (transmembraneactivator and cyclophylin ligand interactor) and BAFF-R (B cellactivation factor receptor, also known as tumor necrosis factor receptorsuperfamily member 13C). Expression of BCMA appears rather late in Bcell differentiation and contributes to the long term survival ofplasmablasts and plasma cells in the bone marrow. BCMA also supportsgrowth and survival of multiple myeloma (MM) cells.

BCMA is mostly known for its functional activity in mediating thesurvival of plasma cells that maintain long-term humoral immunity.

There is a need for having treatment options for solid tumor diseasesrelated to the overexpression of BCMA, such as cancer multiple myeloma,leukemias and lymphomas. The present disclosure provides, in certainembodiments, single domain proteins which specifically bind to BCMA onthe surface of tumor target cells.

The design of the BCMA targeting trispecific proteins described hereinallows the binding domain to BCMA to be flexible in that the bindingdomain to BCMA can be any type of binding domain, including but notlimited to, domains from a monoclonal antibody, a polyclonal antibody, arecombinant antibody, a human antibody, a humanized antibody. In someembodiments, the binding domain to BCMA is a single chain variablefragments (scFv), single-domain antibody such as a heavy chain variabledomain (VH), a light chain variable domain (VL) and a variable domain(VHH) of camelid derived single domain antibody. In other embodiments,the binding domain to BCMA is a non-Ig binding domain, i.e., antibodymimetic, such as anticalins, affilins, affibody molecules, affimers,affitins, alphabodies, avimers, DARPins, fynomers, kunitz domainpeptides, and monobodies. In further embodiments, the binding domain toBCMA is a ligand or peptide that binds to or associates with BCMA. Inyet further embodiments, the binding domain to BCMA is a knottin. In yetfurther embodiments, the binding domain to BCMA is a small molecularentity.

In some embodiments, the BCMA binding domain binds to a proteincomprising the sequence of SEQ ID NO: 469, 470 or 471. In someembodiments, the BCMA binding domain binds to a protein comprising atruncated sequence compared to SEQ ID NO: 469, 470 or 471.

In some embodiments, the BCMA binding domain is an anti-BCMA antibody oran antibody variant. As used herein, the term “antibody variant” refersto variants and derivatives of an antibody described herein. In certainembodiments, amino acid sequence variants of the anti-BCMA antibodiesdescribed herein are contemplated. For example, in certain embodimentsamino acid sequence variants of anti-BCMA antibodies described hereinare contemplated to improve the binding affinity and/or other biologicalproperties of the antibodies. Exemplary method for preparing amino acidvariants include, but are not limited to, introducing appropriatemodifications into the nucleotide sequence encoding the antibody, or bypeptide synthesis. Such modifications include, for example, deletionsfrom, and/or insertions into and/or substitutions of residues within theamino acid sequences of the antibody.

Any combination of deletion, insertion, and substitution can be made toarrive at the final construct, provided that the final constructpossesses the desired characteristics, e.g., antigen-binding. In certainembodiments, antibody variants having one or more amino acidsubstitutions are provided. Sites of interest for substitutionmutagenesis include the CDRs and framework regions. Examples of suchsubstitutions are described below. Amino acid substitutions may beintroduced into an antibody of interest and the products screened for adesired activity, e.g., retained/improved antigen binding, decreasedimmunogenicity, or improved T-cell mediated cytotoxicity (TDCC). Bothconservative and non-conservative amino acid substitutions arecontemplated for preparing the antibody variants.

In another example of a substitution to create a variant anti-BCMAantibody, one or more hypervariable region residues of a parent antibodyare substituted. In general, variants are then selected based onimprovements in desired properties compared to a parent antibody, forexample, increased affinity, reduced affinity, reduced immunogenicity,increased pH dependence of binding.

In some embodiments, the BCMA binding domain of the BCMA targetingtrispecific protein is a single domain antibody such as a heavy chainvariable domain (VH), a variable domain (VHH) of a llama derived sdAb, apeptide, a ligand or a small molecule entity specific for BCMA. In someembodiments, the BCMA binding domain of the BCMA targeting trispecificprotein described herein is any domain that binds to BCMA including butnot limited to domains from a monoclonal antibody, a polyclonalantibody, a recombinant antibody, a human antibody, a humanizedantibody. In certain embodiments, the BCMA binding domain is asingle-domain antibody. In other embodiments, the BCMA binding domain isa peptide. In further embodiments, the BCMA binding domain is a smallmolecule.

Generally, it should be noted that the term single domain antibody asused herein in its broadest sense is not limited to a specificbiological source or to a specific method of preparation. Single domainantibodies are antibodies whose complementary determining regions arepart of a single domain polypeptide. Examples include, but are notlimited to, heavy chain antibodies, antibodies naturally devoid of lightchains, single domain antibodies derived from conventional 4-chainantibodies, engineered antibodies and single domain scaffolds other thanthose derived from antibodies. Single domain antibodies may be any ofthe art, or any future single domain antibodies. Single domainantibodies may be derived from any species including, but not limited tomouse, human, camel, llama, goat, rabbit, bovine. For example, in someembodiments, the single domain antibodies of the disclosure areobtained: (1) by isolating the VHH domain of a naturally occurring heavychain antibody; (2) by expression of a nucleotide sequence encoding anaturally occurring VHH domain; (3) by “humanization” of a naturallyoccurring VHH domain or by expression of a nucleic acid encoding a suchhumanized VHH domain; (4) by “camelization” of a naturally occurring VHdomain from any animal species, and in particular from a species ofmammal, such as from a human being, or by expression of a nucleic acidencoding such a camelized VH domain; (5) by “camelisation” of a “domainantibody” or “Dab”, or by expression of a nucleic acid encoding such acamelized VH domain; (6) by using synthetic or semi-synthetic techniquesfor preparing proteins, polypeptides or other amino acid sequences; (7)by preparing a nucleic acid encoding a single domain antibody usingtechniques for nucleic acid synthesis known in the field, followed byexpression of the nucleic acid thus obtained; and/or (8) by anycombination of one or more of the foregoing.

In one embodiment, a single domain antibody corresponds to the VHHdomains of naturally occurring heavy chain antibodies directed againstBCMA. As further described herein, such VHH sequences can generally begenerated or obtained by suitably immunizing a species of Llama withBCMA, (i.e., so as to raise an immune response and/or heavy chainantibodies directed against BCMA), by obtaining a suitable biologicalsample from said Llama (such as a blood sample, serum sample or sampleof B-cells), and by generating VHH sequences directed against BCMA,starting from said sample, using any suitable technique known in thefield.

In another embodiment, such naturally occurring VHH domains againstBCMA, are obtained from naïve libraries of Camelid VHH sequences, forexample by screening such a library using BCMA, or at least one part,fragment, antigenic determinant or epitope thereof using one or morescreening techniques known in the field. Such libraries and techniquesare for example described in WO 99/37681, WO 01/90190, WO 03/025020 andWO 03/035694. Alternatively, improved synthetic or semi-syntheticlibraries derived from naïve VHH libraries are used, such as VHHlibraries obtained from naïve VHH libraries by techniques such as randommutagenesis and/or CDR shuffling, as for example described in WO00/43507.

In a further embodiment, yet another technique for obtaining VHHsequences directed against BCMA, involves suitably immunizing atransgenic mammal that is capable of expressing heavy chain antibodies(i.e., so as to raise an immune response and/or heavy chain antibodiesdirected against BCMA), obtaining a suitable biological sample from saidtransgenic mammal (such as a blood sample, serum sample or sample ofB-cells), and then generating VHH sequences directed against BCMA,starting from said sample, using any suitable technique known in thefield. For example, for this purpose, the heavy chainantibody-expressing rats or mice and the further methods and techniquesdescribed in WO 02/085945 and in WO 04/049794 can be used.

In some embodiments, an anti-BCMA single domain antibody of the BCMAtargeting trispecific protein comprises a single domain antibody with anamino acid sequence that corresponds to the amino acid sequence of anaturally occurring VHH domain, but that has been “humanized”, i.e., byreplacing one or more amino acid residues in the amino acid sequence ofsaid naturally occurring VHH sequence (and in particular in theframework sequences) by one or more of the amino acid residues thatoccur at the corresponding position(s) in a VH domain from aconventional 4-chain antibody from a human being (e.g., as indicatedabove). This can be performed in a manner known in the field, which willbe clear to the skilled person, for example on the basis of the furtherdescription herein. Again, it should be noted that such humanizedanti-BCMA single domain antibodies of the disclosure are obtained in anysuitable manner known per se (i.e., as indicated under points (1)-(8)above) and thus are not strictly limited to polypeptides that have beenobtained using a polypeptide that comprises a naturally occurring VHHdomain as a starting material. In some additional embodiments, a singledomain anti-BCMA antibody, as described herein, comprises a singledomain antibody with an amino acid sequence that corresponds to theamino acid sequence of a naturally occurring VH domain, but that hasbeen “camelized”, i.e., by replacing one or more amino acid residues inthe amino acid sequence of a naturally occurring VH domain from aconventional 4-chain antibody by one or more of the amino acid residuesthat occur at the corresponding position(s) in a VHH domain of a heavychain antibody. Such “camelizing” substitutions are preferably insertedat amino acid positions that form and/or are present at the VH-VLinterface, and/or at the so-called Camelidae hallmark residues (see forexample WO 94/04678 and Davies and Riechmann (1994 and 1996)).Preferably, the VH sequence that is used as a starting material orstarting point for generating or designing the camelized single domainis preferably a VH sequence from a mammal, more preferably the VHsequence of a human being, such as a VH3 sequence. However, it should benoted that such camelized anti-BCMA single domain antibodies of thedisclosure, in certain embodiments, are obtained in any suitable mannerknown in the field (i.e., as indicated under points (1)-(8) above) andthus are not strictly limited to polypeptides that have been obtainedusing a polypeptide that comprises a naturally occurring VH domain as astarting material. For example, as further described herein, both“humanization” and “camelization” is performed by providing a nucleotidesequence that encodes a naturally occurring VHH domain or VH domain,respectively, and then changing, one or more codons in said nucleotidesequence in such a way that the new nucleotide sequence encodes a“humanized” or “camelized” single domain antibody, respectively. Thisnucleic acid can then be expressed, so as to provide a desired anti-BCMAsingle domain antibody of the disclosure. Alternatively, in otherembodiments, based on the amino acid sequence of a naturally occurringVHH domain or VH domain, respectively, the amino acid sequence of thedesired humanized or camelized anti-BCMA single domain antibody of thedisclosure, respectively, are designed and then synthesized de novousing known techniques for peptide synthesis. In some embodiments, basedon the amino acid sequence or nucleotide sequence of a naturallyoccurring VHH domain or VH domain, respectively, a nucleotide sequenceencoding the desired humanized or camelized anti-BCMA single domainantibody of the disclosure, respectively, is designed and thensynthesized de novo using known techniques for nucleic acid synthesis,after which the nucleic acid thus obtained is expressed in using knownexpression techniques, so as to provide the desired anti-BCMA singledomain antibody of the disclosure.

Other suitable methods and techniques for obtaining the anti-BCMA singledomain antibody of the disclosure and/or nucleic acids encoding thesame, starting from naturally occurring VH sequences or VHH sequencesfor example comprises combining one or more parts of one or morenaturally occurring VH sequences (such as one or more framework (FR)sequences and/or complementarity determining region (CDR) sequences),one or more parts of one or more naturally occurring VHH sequences (suchas one or more FR sequences or CDR sequences), and/or one or moresynthetic or semi-synthetic sequences, in a suitable manner, so as toprovide an anti-BCMA single domain antibody of the disclosure or anucleotide sequence or nucleic acid encoding the same.

In some embodiments, the BCMA binding domain is an anti-BCMA specificantibody comprising a heavy chain variable complementarity determiningregion CDR1, a heavy chain variable CDR2, a heavy chain variable CDR3, alight chain variable CDR1, a light chain variable CDR2, and a lightchain variable CDR3. In some embodiments, the BCMA binding domaincomprises any domain that binds to BCMA including but not limited todomains from a monoclonal antibody, a polyclonal antibody, a recombinantantibody, a human antibody, a humanized antibody, or antigen bindingfragments such as single domain antibodies (sdAb), Fab, Fab′, F(ab)2,and Fv fragments, fragments comprised of one or more CDRs, single-chainantibodies (e.g., single chain Fv fragments (scFv)), disulfidestabilized (dsFv) Fv fragments, heteroconjugate antibodies (e.g.,bispecific antibodies), pFv fragments, heavy chain monomers or dimers,light chain monomers or dimers, and dimers consisting of one heavy chainand one light chain. In some embodiments, the BCMA binding domain is asingle domain antibody. In some embodiments, the anti-BCMA single domainantibody comprises heavy chain variable complementarity determiningregions (CDR), CDR1, CDR2, and CDR3.

In some embodiments, the BCMA binding protein of the present disclosureis a polypeptide comprising an amino acid sequence that is comprised offour framework regions/sequences (f1-f4) interrupted by threecomplementarity determining regions/sequences, as represented by theformula: f1-r1-f2-r2-f3-r3-f4, wherein r1, r2, and r3 arecomplementarity determining regions CDR1, CDR2, and CDR3, respectively,and f1, f2, f3, and f4 are framework residues. The r1 residues of theBCMA binding protein of the present disclosure comprise, for example,amino acid residues 26, 27, 28, 29, 30, 31, 32, 33 and 34; the r2residues of the BCMA binding protein of the present disclosure comprise,for example, amino acid residues, for example, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62 and 63; and the r3 residues of the BCMAbinding protein of the present disclosure comprise, for example, aminoacid residues, for example, 97, 98, 99, 100, 101, 102, 103, 104, 105,106, 107 and 108. In some embodiments, the BCMA binding proteincomprises an amino acid sequence selected from SEQ ID NOs: 346-460.

In one embodiment, the CDR1 does not comprise an amino acid sequence ofSEQ ID NO: 599. In one embodiment, the CDR2 does not comprise an aminoacid sequence of SEQ ID NO: 600. In one embodiment, the CDR3 does notcomprise an amino acid sequence of SEQ ID NO: 601.

In some embodiments, the CDR1 comprises the amino acid sequence as setforth in SEQ ID NO: 1 or a variant thereof having one, two, three, four,five, six, seven, eight, nine, or ten amino acid substitutions. Anexemplary CDR1 comprises the amino acid sequence as set forth in SEQ IDNO: 4. Another exemplary CDR1 comprises the amino acid sequence as setforth in SEQ ID NO: 5. Another exemplary CDR1 comprises the amino acidsequence as set forth in SEQ ID NO: 6. Another exemplary CDR1 comprisesthe amino acid sequence as set forth in SEQ ID NO: 7. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 8.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 9. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 10. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 11. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 12.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 13. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 14. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 15. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 16.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 17. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 18. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 19. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 20.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 21. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 22. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 23. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 24.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 25. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 26. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 27. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 28.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 29. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 30. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 31. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 32.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 33. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 34. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 35. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 36.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 37. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 38. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 39. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 40.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 41. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 42. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 43. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 44.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 45. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 46. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 47. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 48.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 49. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 50. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 51. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 52.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 53. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 54. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 55. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 56.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 57. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 58. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 59. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 60.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 61. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 62. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 63. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 64.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 65. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 66. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 67. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 68.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 69. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 70. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 71. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 72.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 73. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 74. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 75. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 76.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 77. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 78. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 79. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 80.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 81. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 82. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 83. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 84.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 85. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 86. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 87. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 88.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 89. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 90. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 91. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 92.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 93. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 94. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 95. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 96.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 97. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 98. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 99. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 100.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 101. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 102. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 103. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 104.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 105. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 106. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 107. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 108.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 109. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 110. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 111. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 112.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 113. Another exemplary CDR1 comprises the amino acid sequenceas set forth in SEQ ID NO: 114. Another exemplary CDR1 comprises theamino acid sequence as set forth in SEQ ID NO: 115. Another exemplaryCDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 116.Another exemplary CDR1 comprises the amino acid sequence as set forth inSEQ ID NO: 117.

In some embodiments, the CDR2 comprises a sequence as set forth in SEQID NO: 2 or a variant having one, two, three, four, five, six, seven,eight, nine, or ten amino acid substitutions in SEQ ID NO: 2. Anotherexemplary CDR2 comprises the amino acid sequence as set forth in SEQ IDNO: 118. Another exemplary CDR2 comprises the amino acid sequence as setforth in SEQ ID NO: 119. Another exemplary CDR2 comprises the amino acidsequence as set forth in SEQ ID NO: 120. Another exemplary CDR2comprises the amino acid sequence as set forth in SEQ ID NO: 121.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 122. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 123. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 124. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 125.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 126. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 127. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 128. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 129.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 130. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 131. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 132. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 133.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 134. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 135. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 136. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 137.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 138. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 139. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 140. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 141.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 142. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 143. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 144. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 145.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 146. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 147. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 148. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 149.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 150. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 151. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 152. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 153.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 154. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 155. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 156. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 157.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 158. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 159. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 160. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 161.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 162. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 163. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 164. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 165.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 166. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 167. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 168. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 169.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 170. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 171. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 172. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 173.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 174. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 175. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 176. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 177.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 178. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 179. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 180. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 181.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 182. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 183. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 184. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 185.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 186. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 187. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 188. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 189.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 190. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 191. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 192. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 193.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 194. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 195. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 196. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 197.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 198. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 199. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 200. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 201.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 202. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 203. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 204. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 205.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 206. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 207. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 208. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 209.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 210. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 211. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 212. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 213.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 214. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 215. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 216. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 217.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 218. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 219. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 220. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 221.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 222. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 223. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 224. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 225.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 226. Another exemplary CDR2 comprises the amino acid sequenceas set forth in SEQ ID NO: 227. Another exemplary CDR2 comprises theamino acid sequence as set forth in SEQ ID NO: 228. Another exemplaryCDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 229.Another exemplary CDR2 comprises the amino acid sequence as set forth inSEQ ID NO: 230. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 231.

In some embodiments, the CDR3 comprises a sequence as set forth in SEQID NO: 3 or a variant having one, two, three, four, five, six, seven,eight, nine, or ten amino acid substitutions in SEQ ID NO: 3. Anotherexemplary CDR3 comprises the amino acid sequence as set forth in SEQ IDNO: 232. Another exemplary CDR3 comprises the amino acid sequence as setforth in SEQ ID NO: 233. Another exemplary CDR3 comprises the amino acidsequence as set forth in SEQ ID NO: 234. Another exemplary CDR3comprises the amino acid sequence as set forth in SEQ ID NO: 235.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 236. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 237. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 238. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 239.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 240. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 241. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 242. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 243.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 244. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 245. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 246. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 247.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 248. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 249. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 250. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 251.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 252. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 253. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 254. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 255.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 256. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 257. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 258. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 259.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 260. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 261. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 262. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 263.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 264. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 265. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 266. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 267.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 268. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 269. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 270. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 271.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 272. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 273. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 274. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 275.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 276. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 277. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 278. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 279.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 280. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 281. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 282. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 283.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 284. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 285. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 286. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 287.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 288. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 289. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 290. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 291.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 292. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 293. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 294. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 295.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 296. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 297. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 298. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 299.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 300. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 301. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 302. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 303.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 304. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 305. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 306. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 307.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 308. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 309. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 310. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 311.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 312. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 313. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 314. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 315.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 316. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 317. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 318. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 319.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 320. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 321. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 322. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 323.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 324. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 325. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 326. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 327.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 328. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 329. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 330. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 331.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 332. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 333. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 334. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 335.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 336. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 337. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 338. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 339.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 340. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 341. Another exemplary CDR3 comprises theamino acid sequence as set forth in SEQ ID NO: 342. Another exemplaryCDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 343.Another exemplary CDR3 comprises the amino acid sequence as set forth inSEQ ID NO: 344. Another exemplary CDR3 comprises the amino acid sequenceas set forth in SEQ ID NO: 345.

In various embodiments, the BCMA binding protein of the presentdisclosure has a CDR1 that has an amino acid sequence that is at leastabout 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%,about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about100% identical to an amino acid sequence selected from SEQ ID NOs:4-117.

In various embodiments, the BCMA binding protein of the presentdisclosure has a CDR2 that has an amino acid sequence that is at leastabout 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%,about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about100% identical to an amino acid sequence selected from SEQ ID NOs:118-231.

In various embodiments, a complementarity determining region of the BCMAbinding protein of the present disclosure has a CDR3 that has an aminoacid sequence that is at least about 10%, about 20%, about 30%, about40%, about 50%, about 60%, about 70%, about 80%, about 81%, about 82%,about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%,about 96%, about 97%, about 98%, about 99%, or about 100% identical toan amino acid sequence selected from SEQ ID NOs: 232-345.

In various embodiments, a BCMA binding protein of the present disclosurehas an amino acid sequence that is at least about 10%, about 20%, about30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 81%,about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%,about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%identical to an amino acid sequence selected from SEQ ID NOs: 346-460.

In various embodiments, a BCMA binding protein of the present disclosurehas a framework 1 (f1) that has an amino acid sequence that is at leastabout 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about70%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%,about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%,about 99%, or about 100% identical to the amino acid sequence set forthin SEQ ID NO: 461 or SEQ ID NO: 462.

In various embodiments, a BCMA binding protein of the present disclosurehas a framework 2 (f2) that has an amino acid sequence that is at leastabout 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about70%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%,about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%,about 99%, or about 100% identical to the amino acid sequence set forthin SEQ ID NO: 463.

In various embodiments, a BCMA binding protein of the present disclosurehas a framework 3 (f3) that has an amino acid sequence that is at leastabout 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about70%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%,about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%,about 99%, or about 100% identical to the amino acid sequence set forthin SEQ ID NO: 464 or SEQ ID NO: 465.

In various embodiments, a BCMA binding protein of the present disclosurehas a framework 4 (f4) that has an amino acid sequence that is at leastabout 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about70%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%,about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%,about 99%, or about 100% identical to the amino acid sequence set forthin SEQ ID NO: 466 or SEQ ID NO: 467.

In some embodiments, the BCMA binding protein is a single domainantibody comprising the sequence of SEQ ID NO: 346. In some embodiments,the BCMA binding protein is a single domain antibody comprising thesequence of SEQ ID NO: 347. In some embodiments, the BCMA bindingprotein is a single domain antibody comprising the sequence of SEQ IDNO: 348. In some embodiments, the BCMA binding protein is a singledomain antibody comprising the sequence of SEQ ID NO: 349. In someembodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 350. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 351. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 352. Insome embodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 353. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 354. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 355. Insome embodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 356. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 357. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 358. Insome embodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 359.

In some embodiments, the BCMA binding protein is a single domainantibody comprising the sequence of SEQ ID NO: 360. In some embodiments,the BCMA binding protein is a single domain antibody comprising thesequence of SEQ ID NO: 361. In some embodiments, the BCMA bindingprotein is a single domain antibody comprising the sequence of SEQ IDNO: 362. In some embodiments, the BCMA binding protein is a singledomain antibody comprising the sequence of SEQ ID NO: 363. In someembodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 364. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 365. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 366. Insome embodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 367. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 368. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 369.

In some embodiments, the BCMA binding protein is a single domainantibody comprising the sequence of SEQ ID NO: 370. In some embodiments,the BCMA binding protein is a single domain antibody comprising thesequence of SEQ ID NO: 371. In some embodiments, the BCMA bindingprotein is a single domain antibody comprising the sequence of SEQ IDNO: 372. In some embodiments, the BCMA binding protein is a singledomain antibody comprising the sequence of SEQ ID NO: 373. In someembodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 374. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 375. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 376. Insome embodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 377. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 378. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 379.

In some embodiments, the BCMA binding protein is a single domainantibody comprising the sequence of SEQ ID NO: 380. In some embodiments,the BCMA binding protein is a single domain antibody comprising thesequence of SEQ ID NO: 381. In some embodiments, the BCMA bindingprotein is a single domain antibody comprising the sequence of SEQ IDNO: 382. In some embodiments, the BCMA binding protein is a singledomain antibody comprising the sequence of SEQ ID NO: 383. In someembodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 384. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 385. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 386. Insome embodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 387. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 388. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 389.

In some embodiments, the BCMA binding protein is a single domainantibody comprising the sequence of SEQ ID NO: 390. In some embodiments,the BCMA binding protein is a single domain antibody comprising thesequence of SEQ ID NO: 391. In some embodiments, the BCMA bindingprotein is a single domain antibody comprising the sequence of SEQ IDNO: 392. In some embodiments, the BCMA binding protein is a singledomain antibody comprising the sequence of SEQ ID NO: 393. In someembodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 394. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 395. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 396. Insome embodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 397. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 398. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 399.

In some embodiments, the BCMA binding protein is a single domainantibody comprising the sequence of SEQ ID NO: 400. In some embodiments,the BCMA binding protein is a single domain antibody comprising thesequence of SEQ ID NO: 401. In some embodiments, the BCMA bindingprotein is a single domain antibody comprising the sequence of SEQ IDNO: 402. In some embodiments, the BCMA binding protein is a singledomain antibody comprising the sequence of SEQ ID NO: 403. In someembodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 404. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 405. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 406. Insome embodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 407. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 408. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 409.

In some embodiments, the BCMA binding protein is a single domainantibody comprising the sequence of SEQ ID NO: 410. In some embodiments,the BCMA binding protein is a single domain antibody comprising thesequence of SEQ ID NO: 411. In some embodiments, the BCMA bindingprotein is a single domain antibody comprising the sequence of SEQ IDNO: 412. In some embodiments, the BCMA binding protein is a singledomain antibody comprising the sequence of SEQ ID NO: 413. In someembodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 414. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 415. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 416. Insome embodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 417. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 418. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 419.

In some embodiments, the BCMA binding protein is a single domainantibody comprising the sequence of SEQ ID NO: 420. In some embodiments,the BCMA binding protein is a single domain antibody comprising thesequence of SEQ ID NO: 421. In some embodiments, the BCMA bindingprotein is a single domain antibody comprising the sequence of SEQ IDNO: 422. In some embodiments, the BCMA binding protein is a singledomain antibody comprising the sequence of SEQ ID NO: 423. In someembodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 424. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 425. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 426. Insome embodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 427. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 428. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 429.

In some embodiments, the BCMA binding protein is a single domainantibody comprising the sequence of SEQ ID NO: 430. In some embodiments,the BCMA binding protein is a single domain antibody comprising thesequence of SEQ ID NO: 431. In some embodiments, the BCMA bindingprotein is a single domain antibody comprising the sequence of SEQ IDNO: 432. In some embodiments, the BCMA binding protein is a singledomain antibody comprising the sequence of SEQ ID NO: 433. In someembodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 434. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 435. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 436. Insome embodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 437. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 438. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 439.

In some embodiments, the BCMA binding protein is a single domainantibody comprising the sequence of SEQ ID NO: 440. In some embodiments,the BCMA binding protein is a single domain antibody comprising thesequence of SEQ ID NO: 441. In some embodiments, the BCMA bindingprotein is a single domain antibody comprising the sequence of SEQ IDNO: 442. In some embodiments, the BCMA binding protein is a singledomain antibody comprising the sequence of SEQ ID NO: 443. In someembodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 444. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 445. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 446. Insome embodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 447. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 448. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 449.

In some embodiments, the BCMA binding protein is a single domainantibody comprising the sequence of SEQ ID NO: 450. In some embodiments,the BCMA binding protein is a single domain antibody comprising thesequence of SEQ ID NO: 451. In some embodiments, the BCMA bindingprotein is a single domain antibody comprising the sequence of SEQ IDNO: 452. In some embodiments, the BCMA binding protein is a singledomain antibody comprising the sequence of SEQ ID NO: 453. In someembodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 454. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 455. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 456. Insome embodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 457. In some embodiments, the BCMAbinding protein is a single domain antibody comprising the sequence ofSEQ ID NO: 458. In some embodiments, the BCMA binding protein is asingle domain antibody comprising the sequence of SEQ ID NO: 459. Insome embodiments, the BCMA binding protein is a single domain antibodycomprising the sequence of SEQ ID NO: 460.

A BCMA binding protein described herein can bind to human BCMA with ahKd ranges from about 0.1 nM to about 500 nM. In some embodiments, thehKd ranges from about 0.1 nM to about 450 nM. In some embodiments, thehKd ranges from about 0.1 nM to about 400 nM. In some embodiments, thehKd ranges from about 0.1 nM to about 350 nM. In some embodiments, thehKd ranges from about 0.1 nM to about 300 nM. In some embodiments, thehKd ranges from about 0.1 nM to about 250 nM. In some embodiments, thehKd ranges from about 0.1 nM to about 200 nM. In some embodiments, thehKd ranges from about 0.1 nM to about 150 nM. In some embodiments, thehKd ranges from about 0.1 nM to about 100 nM. In some embodiments, thehKd ranges from about 0.1 nM to about 90 nM. In some embodiments, thehKd ranges from about 0.2 nM to about 80 nM. In some embodiments, thehKd ranges from about 0.3 nM to about 70 nM. In some embodiments, thehKd ranges from about 0.4 nM to about 50 nM. In some embodiments, thehKd ranges from about 0.5 nM to about 30 nM. In some embodiments, thehKd ranges from about 0.6 nM to about 10 nM. In some embodiments, thehKd ranges from about 0.7 nM to about 8 nM. In some embodiments, the hKdranges from about 0.8 nM to about 6 nM. In some embodiments, the hKdranges from about 0.9 nM to about 4 nM. In some embodiments, the hKdranges from about 1 nM to about 2 nM.

In some embodiments, any of the foregoing BCMA binding domains areaffinity peptide tagged for ease of purification. In some embodiments,the affinity peptide tag is six consecutive histidine residues, alsoreferred to as a His tag or 6X-his (His-His-His-His-His-His; SEQ ID NO:471).

In certain embodiments, the BCMA binding domains of the presentdisclosure preferentially bind membrane bound BCMA over soluble BCMA.Membrane bound BCMA refers to the presence of BCMA in or on the cellmembrane surface of a cell that expresses BCMA. Soluble BCMA refers toBCMA that is no longer on in or on the cell membrane surface of a cellthat expresses or expressed BCMA. In certain instances, the soluble BCMAis present in the blood and/or lymphatic circulation in a subject. Inone embodiment, the BCMA binding domains bind membrane-bound BCMA atleast 5 fold, 10 fold, 15 fold, 20 fold, 25 fold, 30 fold, 40 fold, 50fold, 100 fold, 500 fold, or 1000 fold greater than soluble BCMA. In oneembodiment, the BCMA targeting trispecific antigen binding proteins ofthe present disclosure preferentially bind membrane-bound BCMA 30 foldgreater than soluble BCMA. Determining the preferential binding of anantigen binding protein to membrane bound BCMA over soluble BCMA can bereadily determined using assays well known in the art.

Trispecific Proteins

A BCMA binding trispecific protein comprises an amino acid sequenceselected from the group consisting of SEQ ID NO: 483-597.

In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 483. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 484.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 485. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 486.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 487. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 488.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 489. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 490.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 491. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 492.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 493. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 494.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 495. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 496.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 497. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 498.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 499.

In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 500. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 501.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 502. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 503.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 504. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 505.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 506. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 507.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 508. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 509.

In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 510. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 511.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 512. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 513.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 514. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 515.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 516. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 517.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 518. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 519.

In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 520. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 521.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 522. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 523.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 524. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 525.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 526. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 527.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 528. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 529.

In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 530. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 531.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 532. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 533.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 534. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 535.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 536. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 537.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 538. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 539.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 540.

In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 541. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 542.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 543. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 544.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 545. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 546.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 547. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 5048.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 549. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 550.

In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 551. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 552.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 553. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 554.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 555. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 556.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 557. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 558.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 559.

In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 560. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 561.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 562. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 563.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 564. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 565.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 566. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 567.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 568. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 569.

In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 570. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 571.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 572. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 573.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 574. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 575.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 576. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 577.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 578. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 579.

In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 580. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 581.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 582. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 583.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 584. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 585.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 586. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 587.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 588. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 589.

In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 590. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 591.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 592. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 593.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 594. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 595.In one example, a BCMA binding trispecific protein comprises an aminoacid sequence of SEQ ID NO: 596. In one example, a BCMA bindingtrispecific protein comprises an amino acid sequence of SEQ ID NO: 597.

Polynucleotides Encoding BCMA Targeting Trispecific Proteins

Also provided, in some embodiments, are polynucleotide moleculesencoding an anti-BCMA trispecific binding protein described herein. Insome embodiments, the polynucleotide molecules are provided as a DNAconstruct. In other embodiments, the polynucleotide molecules areprovided as a messenger RNA transcript.

The polynucleotide molecules are constructed by known methods such as bycombining the genes encoding the three binding domains either separatedby peptide linkers or, in other embodiments, directly linked by apeptide bond, into a single genetic construct operably linked to asuitable promoter, and optionally a suitable transcription terminator,and expressing it in bacteria or other appropriate expression systemsuch as, for example CHO cells. In the embodiments where the BCMAbinding domain is a small molecule, the polynucleotides contain genesencoding the CD3 binding domain and the half-life extension domain. Inthe embodiments where the half-life extension domain is a smallmolecule, the polynucleotides contain genes encoding the domains thatbind to CD3 and BCMA. Depending on the vector system and host utilized,any number of suitable transcription and translation elements, includingconstitutive and inducible promoters, may be used. The promoter isselected such that it drives the expression of the polynucleotide in therespective host cell.

In some embodiments, the polynucleotide is inserted into a vector,preferably an expression vector, which represents a further embodiment.This recombinant vector can be constructed according to known methods.Vectors of particular interest include plasmids, phagemids, phagederivatives, virii (e.g., retroviruses, adenoviruses, adeno-associatedviruses, herpes viruses, lentiviruses, and the like), and cosmids.

A variety of expression vector/host systems may be utilized to containand express the polynucleotide encoding the polypeptide of the describedtrispecific antigen-binding protein. Examples of expression vectors forexpression in E. coli are pSKK (Le Gall et al., J Immunol Methods.(2004) 285(1):111-27) or pcDNA5 (Invitrogen) for expression in mammaliancells.

Thus, the BCMA targeting trispecific proteins as described herein, insome embodiments, are produced by introducing a vector encoding theprotein as described above into a host cell and culturing said host cellunder conditions whereby the protein domains are expressed, may beisolated and, optionally, further purified.

Integration into Chimeric Antigen Receptors (CAR)

The BCMA targeting trispecific antigen binding proteins of the presentdisclosure can, in certain examples, be incorporated into a chimericantigen receptor (CAR). An engineered immune effector cell, e.g., a Tcell or NK cell, can be used to express a CAR that includes an anti-BCMAtargeting trispecific protein containing an anti-BCMA single domainantibody as described herein. In one embodiment, the CAR including ananti-BCMA targeting trispecific protein as described herein is connectedto a transmembrane domain via a hinge region, and further acostimulatory domain, e.g., a functional signaling domain obtained fromOX40, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), or4-1BB. In some embodiments, the CAR further comprises a sequenceencoding a intracellular signaling domain, such as 4-1BB and/or CD3zeta.

BCMA Trispecific Protein Modifications

The BCMA targeting trispecific proteins described herein encompassderivatives or analogs in which (i) an amino acid is substituted with anamino acid residue that is not one encoded by the genetic code, (ii) themature polypeptide is fused with another compound such as polyethyleneglycol, or (iii) additional amino acids are fused to the protein, suchas a leader or secretory sequence or a sequence for purification of theprotein.

Typical modifications include, but are not limited to, acetylation,acylation, ADP-ribosylation, amidation, covalent attachment of flavin,covalent attachment of a heme moiety, covalent attachment of anucleotide or nucleotide derivative, covalent attachment of a lipid orlipid derivative, covalent attachment of phosphatidylinositol,cross-linking, cyclization, disulfide bond formation, demethylation,formation of covalent crosslinks, formation of cystine, formation ofpyroglutamate, formylation, gamma carboxylation, glycosylation, GPIanchor formation, hydroxylation, iodination, methylation,myristoylation, oxidation, proteolytic processing, phosphorylation,prenylation, racemization, selenoylation, sulfation, transfer-RNAmediated addition of amino acids to proteins such as arginylation, andubiquitination.

Modifications are made anywhere in BCMA targeting trispecific proteinsdescribed herein, including the peptide backbone, the amino acidside-chains, and the amino or carboxyl termini. Certain common peptidemodifications that are useful for modification of BCMA targetingtrispecific proteins include glycosylation, lipid attachment, sulfation,gamma-carboxylation of glutamic acid residues, hydroxylation, blockageof the amino or carboxyl group in a polypeptide, or both, by a covalentmodification, and ADP-ribosylation.

Pharmaceutical Compositions

Also provided, in some embodiments, are pharmaceutical compositionscomprising an anti-BCMA trispecific binding protein described herein, avector comprising the polynucleotide encoding the polypeptide of theBCMA targeting trispecific proteins or a host cell transformed by thisvector and at least one pharmaceutically acceptable carrier. The term“pharmaceutically acceptable carrier” includes, but is not limited to,any carrier that does not interfere with the effectiveness of thebiological activity of the ingredients and that is not toxic to thepatient to whom it is administered. Examples of suitable pharmaceuticalcarriers are well known in the art and include phosphate buffered salinesolutions, water, emulsions, such as oil/water emulsions, various typesof wetting agents, sterile solutions etc. Such carriers can beformulated by conventional methods and can be administered to thesubject at a suitable dose. Preferably, the compositions are sterile.These compositions may also contain adjuvants such as preservative,emulsifying agents and dispersing agents. Prevention of the action ofmicroorganisms may be ensured by the inclusion of various antibacterialand antifungal agents. A further embodiment provides one or more of theabove described BCMA targeting trispecific proteins packaged inlyophilized form, or packaged in an aqueous medium.

In some embodiments of the pharmaceutical compositions, the BCMAtargeting trispecific proteins described herein are encapsulated innanoparticles. In some embodiments, the nanoparticles are fullerenes,liquid crystals, liposome, quantum dots, superparamagneticnanoparticles, dendrimers, or nanorods. In other embodiments of thepharmaceutical compositions, the BCMA trispecific antigen-bindingprotein is attached to liposomes. In some instances, the BCMAtrispecific antigen-binding proteins are conjugated to the surface ofliposomes. In some instances, the BCMA trispecific antigen-bindingproteins are encapsulated within the shell of a liposome. In someinstances, the liposome is a cationic liposome.

The BCMA targeting trispecific proteins described herein arecontemplated for use as a medicament. Administration is effected bydifferent ways, e.g. by intravenous, intraperitoneal, subcutaneous,intramuscular, topical or intradermal administration. In someembodiments, the route of administration depends on the kind of therapyand the kind of compound contained in the pharmaceutical composition.The dosage regimen will be determined by the attending physician andother clinical factors. Dosages for any one patient depends on manyfactors, including the patient's size, body surface area, age, sex, theparticular compound to be administered, time and route ofadministration, the kind of therapy, general health and other drugsbeing administered concurrently. An “effective dose” refers to amountsof the active ingredient that are sufficient to affect the course andthe severity of the disease, leading to the reduction or remission ofsuch pathology and may be determined using known methods.

In some embodiments, the BCMA targeting trispecific proteins of thisdisclosure are administered at a dosage of up to 10 mg/kg at a frequencyof once a week. In some cases, the dosage ranges from about 1 ng/kg toabout 10 mg/kg. In some embodiments, the dose is from about 1 ng/kg toabout 10 ng/kg, about 5 ng/kg to about 15 ng/kg, about 12 ng/kg to about20 ng/kg, about 18 ng/kg to about 30 ng/kg, about 25 ng/kg to about 50ng/kg, about 35 ng/kg to about 60 ng/kg, about 45 ng/kg to about 70ng/kg, about 65 ng/kg to about 85 ng/kg, about 80 ng/kg to about 1μg/kg, about 0.5 μg/kg to about 5 μg/kg, about 2 μg/kg to about 10μg/kg, about 7 μg/kg to about 15 μg/kg, about 12 μg/kg to about 25μg/kg, about 20 μg/kg to about 50 μg/kg, about 35 μg/kg to about 70μg/kg, about 45 μg/kg to about 80 μg/kg, about 65 μg/kg to about 90μg/kg, about 85 μg/kg to about 0.1 mg/kg, about 0.095 mg/kg to about 10mg/kg. In some cases, the dosage is about 0.1 mg/kg to about 0.2 mg/kg;about 0.25 mg/kg to about 0.5 mg/kg, about 0.45 mg/kg to about 1 mg/kg,about 0.75 mg/kg to about 3 mg/kg, about 2.5 mg/kg to about 4 mg/kg,about 3.5 mg/kg to about 5 mg/kg, about 4.5 mg/kg to about 6 mg/kg,about 5.5 mg/kg to about 7 mg/kg, about 6.5 mg/kg to about 8 mg/kg,about 7.5 mg/kg to about 9 mg/kg, or about 8.5 mg/kg to about 10 mg/kg.The frequency of administration, in some embodiments, is about less thandaily, every other day, less than once a day, twice a week, weekly, oncein 7 days, once in two weeks, once in two weeks, once in three weeks,once in four weeks, or once a month. In some cases, the frequency ofadministration is weekly. In some cases, the frequency of administrationis weekly and the dosage is up to 10 mg/kg. In some cases, duration ofadministration is from about 1 day to about 4 weeks or longer.

Methods of Treatment

In certain embodiments, the BCMA targeting trispecific proteins of thedisclosure reduce the growth of tumor cells in vivo when administered toa subject who has tumor cells that express BCMA. Measurement of thereduction of the growth of tumor cells can be determined by multipledifferent methodologies well known in the art. Non-limiting examplesinclude direct measurement of tumor dimension, measurement of excisedtumor mass and comparison to control subjects, measurement via imagingtechniques (e.g., CT or Mill) that may or may not use isotopes orluminescent molecules (e.g., luciferase) for enhanced analysis, and thelike. In specific embodiments, administration of the trispecificproteins of the disclosure results in a reduction of in vivo growth oftumor cells as compared to a control antigen binding agent by at leastabout 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, with an about100% reduction in tumor growth indicating a complete response anddisappearance of the tumor. In further embodiments, administration ofthe trispecific proteins of the disclosure results in a reduction of invivo growth of tumor cells as compared to a control antigen bindingagent by about 50-100%, about 75-100% or about 90-100%. In furtherembodiments, administration of the trispecific proteins of thedisclosure results in a reduction of in vivo growth of tumor cells ascompared to a control antigen binding agent by about 50-60%, about60-70%, about 70-80%, about 80-90%, or about 90-100%.

Also provided herein, in some embodiments, are methods and uses forstimulating the immune system of an individual in need thereofcomprising administration of an anti-BCMA targeting trispecific proteinas described herein. In some instances, the administration of ananti-BCMA targeting trispecific protein described herein induces and/orsustains cytotoxicity towards a cell expressing a target antigen.

Also provided herein, in some embodiments, are methods and uses forstimulating the immune system of an individual in need thereofcomprising administration of a BCMA binding protein as described herein.In some instances, the administration of a BCMA binding proteindescribed herein induces and/or sustains cytotoxicity towards a cellexpressing a target antigen. In some instances, the cell expressing atarget antigen is a terminally differentiated B cell that is a cancer ortumor cell, or a metastatic cancer or tumor cell.

Also provided herein are methods and uses for a treatment of a disease,disorder or condition associated with BCMA comprising administering toan individual in need thereof a BCMA binding protein or a multispecificbinding protein comprising the BCMA binding protein described herein.

Diseases, disorders or conditions associated with BCMA include, but arenot limited to, a cancer or a metastasis that is of a B cell lineage.

Cancers that can be treated, prevented, or managed by the BCMA bindingproteins of the present disclosure, and methods of using them, includebut are not limited to a primary cancer or a metastatic cancer.

Examples of such leukemias include, but are not limited to: acutelymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chroniclymphocytic leukemia (CLL) and chronic myeloid leukemia (CIVIL), as wellas a number of less common types such as, for example, Hairy cellleukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), Large granularlymphocytic leukemia and Adult T-cell leukemia, etc. Acute lymphoblasticleukemia (ALL) subtypes to be treated include, but are not limited to,precursor B acute lymphoblastic leukemia, precursor T acutelymphoblastic leukemia, Burkitt's leukemia, and acute biphenotypicleukemia. Chronic lymphocytic leukemia (CLL) subtypes to be treatedinclude, but are not limited to, B-cell prolymphocytic leukemia. Acutemyelogenous leukemia (AML) subtypes to be treated include, but are notlimited to, acute promyelocytic leukemia, acute myeloblastic leukemia,and acute megakaryoblastic leukemia. Chronic myelogenous leukemia(CIVIL) subtypes to be treated include, but are not limited to, chronicmyelomonocytic leukemia.

Examples of a lymphoma to be treated with the subject methods include,but not limited to Hodgkin's disease, non-Hodgkin's disease, or anysubtype of lymphoma.

Examples of such multiple myelomas include, but are not limited to, amultiple myeloma of the bone or other tissues including, for example, asmoldering multiple myeloma, a non-secretory myeloma, a osteoscleroticmyeloma, etc.

For a review of such disorders, see Fishman et al., 1985, Medicine, 2dEd., J.B. Lippincott Co., Philadelphia and Murphy et al., 1997, InformedDecisions: The Complete Book of Cancer Diagnosis, Treatment, andRecovery, Viking Penguin, Penguin Books U.S.A., Inc., United States ofAmerica).

As used herein, in some embodiments, “treatment” or “treating” or“treated” refers to therapeutic treatment wherein the object is to slow(lessen) an undesired physiological condition, disorder or disease, orto obtain beneficial or desired clinical results. For the purposesdescribed herein, beneficial or desired clinical results include, butare not limited to, alleviation of symptoms; diminishment of the extentof the condition, disorder or disease; stabilization (i.e., notworsening) of the state of the condition, disorder or disease; delay inonset or slowing of the progression of the condition, disorder ordisease; amelioration of the condition, disorder or disease state; andremission (whether partial or total), whether detectable orundetectable, or enhancement or improvement of the condition, disorderor disease. Treatment includes eliciting a clinically significantresponse without excessive levels of side effects. Treatment alsoincludes prolonging survival as compared to expected survival if notreceiving treatment. In other embodiments, “treatment” or “treating” or“treated” refers to prophylactic measures, wherein the object is todelay onset of or reduce severity of an undesired physiologicalcondition, disorder or disease, such as, for example is a person who ispredisposed to a disease (e.g., an individual who carries a geneticmarker for a disease such as breast cancer).

In some embodiments of the methods described herein, the BCMA targetingtrispecific proteins as described herein are administered in combinationwith an agent for treatment of the particular disease, disorder orcondition. Agents include, but are not limited to, therapies involvingantibodies, small molecules (e.g., chemotherapeutics), hormones(steroidal, peptide, and the like), radiotherapies (γ-rays, X-rays,and/or the directed delivery of radioisotopes, microwaves, UV radiationand the like), gene therapies (e.g., antisense, retroviral therapy andthe like) and other immunotherapies. In some embodiments, an anti-BCMAtargeting trispecific protein as described herein is administered incombination with anti-diarrheal agents, anti-emetic agents, analgesics,opioids and/or non-steroidal anti-inflammatory agents. In someembodiments, an anti-BCMA targeting trispecific protein as describedherein is administered in combination with anti-cancer agents.

Non-limiting examples of anti-cancer agents that can be used in thevarious embodiments of the disclosure, including pharmaceuticalcompositions and dosage forms and kits of the disclosure, include:acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin;aldesleukin; altretamine; ambomycin; ametantrone acetate;aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase;asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa;bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin;bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; interleukin II (includingrecombinant interleukin II, or rIL2), interferon alpha-2a; interferonalpha-2b; interferon alpha-n1 interferon alpha-n3; interferon beta-I a;interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotideacetate; letrozole; leuprolide acetate; liarozole hydrochloride;lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol;maytansine; mechlorethamine hydrochloride; megestrol acetate;melengestrol acetate; melphalan; menogaril; mercaptopurine;methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide;mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper;mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole;nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin;pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan;piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium;porfiromycin; prednimustine; procarbazine hydrochloride; puromycin;puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol;safingol hydrochloride; semustine; simtrazene; sparfosate sodium;sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin;streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium;tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinzolidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride. Other examples of anti-cancer drugs include, but are notlimited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil;abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin;aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox;amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide;anastrozole; andrographolide; angiogenesis inhibitors; antagonist D;antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1;antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;antisense oligonucleotides; aphidicolin glycinate; apoptosis genemodulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinaseinhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine;droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin;epristeride; estramustine analogue; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-I receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; HMG-CoA reductase inhibitor (suchas but not limited to, Lovastatin, Pravastatin, Fluvastatin, Statin,Simvastatin, and Atorvastatin); loxoribine; lurtotecan; lutetiumtexaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A;marimastat; masoprocol; maspin; matrilysin inhibitors; matrixmetalloproteinase inhibitors; menogaril; merbarone; meterelin;methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine;mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol;mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B 1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen binding protein; sizofiran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;VITAXIN®; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer. Additional anti-cancer drugs are 5-fluorouracil andleucovorin. These two agents are particularly useful when used inmethods employing thalidomide and a topoisomerase inhibitor. In someembodiments, the anti-BCMA targeting trispecific protein of the presentdisclosure is used in combination with gemcitabine.

In some embodiments, the anti-BCMA targeting trispecific protein asdescribed herein is administered before, during, or after surgery.

In some embodiments, the anti-cancer agent is conjugated via anysuitable means to the trispecific protein.

Methods of Detection of BCMA Expression and Diagnosis of BCMA AssociatedCancer

According to another embodiment of the disclosure, kits for detectingexpression of BCMA in vitro and/or in vivo are provided. The kitsinclude the foregoing BCMA targeting trispecific proteins (e.g., atrispecific protein containing a labeled anti-BCMA single domainantibody or antigen binding fragments thereof), and one or morecompounds for detecting the label. In some embodiments, the label isselected from the group consisting of a fluorescent label, an enzymelabel, a radioactive label, a nuclear magnetic resonance active label, aluminescent label, and a chromophore label.

In some cases, BCMA expression is detected in a biological sample. Thesample can be any sample, including, but not limited to, tissue frombiopsies, autopsies and pathology specimens. Biological samples alsoinclude sections of tissues, for example, frozen sections taken forhistological purposes. Biological samples further include body fluids,such as blood, serum, plasma, sputum, spinal fluid or urine. Abiological sample is typically obtained from a mammal, such as a humanor non-human primate.

Samples to be obtained for use in an assay described herein includetissues and bodily fluids may be processed using conventional means inthe art (e.g., homogenization, serum isolation, etc.). Accordingly, asample obtained from a patient is transformed prior to use in an assaydescribed herein. BCMA, if present in the sample, is further transformedin the methods described herein by virtue of binding to, for example, anantibody.

In one embodiment, provided is a method of determining if a subject hascancer by contacting a sample from the subject with an anti-BCMA singledomain antibody as disclosed herein; and detecting binding of the singledomain antibody to the sample. An increase in binding of the antibody tothe sample as compared to binding of the antibody to a control sampleidentifies the subject as having cancer.

In another embodiment, provided is a method of confirming a diagnosis ofcancer in a subject by contacting a sample from a subject diagnosed withcancer with an anti-BCMA single domain antibody as disclosed herein; anddetecting binding of the antibody to the sample. An increase in bindingof the antibody to the sample as compared to binding of the antibody toa control sample confirms the diagnosis of cancer in the subject.

In some examples of the disclosed methods, the BCMA single domainantibody of the trispecific protein is directly labeled.

In some examples, the methods further include contacting a secondantibody that specifically binds the anti-BCMA single domain antibodywith the sample; and detecting the binding of the second antibody. Anincrease in binding of the second antibody to the sample as compared tobinding of the second antibody to a control sample detects cancer in thesubject or confirms the diagnosis of cancer in the subject.

In some cases, the cancer is a leukemia, a lymphoma, a multiple myeloma,or any other type of cancer that expresses BCMA.

In some examples, the control sample is a sample from a subject withoutcancer. In particular examples, the sample is a blood or tissue sample.

In some cases, the antibody that binds (for example specifically binds)BCMA is directly labeled with a detectable label. In another embodiment,the antibody that binds (for example, specifically binds) BCMA (thefirst antibody) is unlabeled and a second antibody or other moleculethat can bind the antibody that specifically binds BCMA is labeled. Asecond antibody is chosen such that it is able to specifically bind thespecific species and class of the first antibody. For example, if thefirst antibody is a llama IgG, then the secondary antibody may be ananti-llama-IgG. Other molecules that can bind to antibodies include,without limitation, Protein A and Protein G, both of which are availablecommercially. Suitable labels for the antibody or secondary antibody aredescribed above, and include various enzymes, prosthetic groups,fluorescent materials, luminescent materials, magnetic agents andradioactive materials. Non-limiting examples of suitable enzymes includehorseradish peroxidase, alkaline phosphatase, beta-galactosidase, oracetylcholinesterase. Non-limiting examples of suitable prosthetic groupcomplexes include streptavidin/biotin and avidin/biotin. Non-limitingexamples of suitable fluorescent materials include umbelliferone,fluorescein, fluorescein isothiocyanate, rhodamine,dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin. Anon-limiting exemplary luminescent material is luminol; a non-limitingexemplary a magnetic agent is gadolinium, and non-limiting exemplaryradioactive labels include 125I, 131I, 35S or 3H.

In an alternative embodiment, BCMA can be assayed in a biological sampleby a competition immunoassay utilizing BCMA standards labeled with adetectable substance and an unlabeled antibody that specifically bindsBCMA. In this assay, the biological sample, the labeled BCMA standardsand the antibody that specifically bind BCMA are combined and the amountof labeled BCMA standard bound to the unlabeled antibody is determined.The amount of BCMA in the biological sample is inversely proportional tothe amount of labeled BCMA standard bound to the antibody thatspecifically binds BCMA.

The immunoassays and method disclosed herein can be used for a number ofpurposes. In one embodiment, the antibody that specifically binds BCMAmay be used to detect the production of BCMA in cells in cell culture.In another embodiment, the antibody can be used to detect the amount ofBCMA in a biological sample, such as a tissue sample, or a blood orserum sample. In some examples, the BCMA is cell-surface BCMA. In otherexamples, the BCMA is soluble BCMA (e.g., BCMA in a cell culturesupernatant or soluble BCMA in a body fluid sample, such as a blood orserum sample).

In one embodiment, a kit is provided for detecting BCMA in a biologicalsample, such as a blood sample or tissue sample. For example, to confirma cancer diagnosis in a subject, a biopsy can be performed to obtain atissue sample for histological examination. Alternatively, a bloodsample can be obtained to detect the presence of soluble BCMA protein orfragment. Kits for detecting a polypeptide will typically comprise asingle domain antibody, according to the present disclosure, thatspecifically binds BCMA. In some embodiments, an antibody fragment, suchas a scFv fragment, a VH domain, or a Fab is included in the kit. In afurther embodiment, the antibody is labeled (for example, with afluorescent, radioactive, or an enzymatic label).

In one embodiment, a kit includes instructional materials disclosingmeans of use of an antibody that binds BCMA. The instructional materialsmay be written, in an electronic form (such as a computer diskette orcompact disk) or may be visual (such as video files), or providedthrough an electronic network, for example, over the internet, WorldWide Web, an intranet, or other network. The kits may also includeadditional components to facilitate the particular application for whichthe kit is designed. Thus, for example, the kit may additionally containmeans of detecting a label (such as enzyme substrates for enzymaticlabels, filter sets to detect fluorescent labels, appropriate secondarylabels such as a secondary antibody, or the like). The kits mayadditionally include buffers and other reagents routinely used for thepractice of a particular method. Such kits and appropriate contents arewell known to those of skill in the art.

In one embodiment, the diagnostic kit comprises an immunoassay. Althoughthe details of the immunoassays may vary with the particular formatemployed, the method of detecting BCMA in a biological sample generallyincludes the steps of contacting the biological sample with an antibodywhich specifically reacts, under immunologically reactive conditions, toa BCMA polypeptide. The antibody is allowed to specifically bind underimmunologically reactive conditions to form an immune complex, and thepresence of the immune complex (bound antibody) is detected directly orindirectly.

Methods of determining the presence or absence of a cell surface markerare well known in the art. For example, the antibodies can be conjugatedto other compounds including, but not limited to, enzymes, magneticbeads, colloidal magnetic beads, haptens, fluorochromes, metalcompounds, radioactive compounds or drugs. The antibodies can also beutilized in immunoassays such as but not limited to radioimmunoassays(RIAs), ELISA, or immunohistochemical assays. The antibodies can also beused for fluorescence activated cell sorting (FACS). FACS employs aplurality of color channels, low angle and obtuse light-scatteringdetection channels, and impedance channels, among other moresophisticated levels of detection, to separate or sort cells (see U.S.Pat. No. 5,061,620). Any of the single domain antibodies that bind BCMA,as disclosed herein, can be used in these assays. Thus, the antibodiescan be used in a conventional immunoassay, including, withoutlimitation, an ELISA, an RIA, FACS, tissue immunohistochemistry, Westernblot or immunoprecipitation.

EXAMPLES

The application may be better understood by reference to the followingnon-limiting examples, which are provided as exemplary embodiments ofthe application. The following examples are presented in order to morefully illustrate embodiments and should in no way be construed, however,as limiting the broad scope of the application.

Example 1 Ability of an Exemplar BCMA Targeting Trispecific Protein toMediate T Cell Killing of Cancer Cells Expressing BCMA, in TDCC (T CellDependent Cell Cytotoxic) Assays

Protein Production

Sequences of BCMA targeting trispecific molecules, containing a BCMAbinding protein according to the present disclosure, were cloned intomammalian expression vector pcDNA 3.4 (Invitrogen) preceded by a leadersequence and followed by a 6× Histidine Tag (SEQ ID NO: 471). EXPI293™cells (Life Technologies A14527) were maintained in suspension inOptimum Growth Flasks (Thomson) between 0.2 to 8×1e6 cells/mL inEXPI293™ media. Purified plasmid DNA was transfected into EXPI293™ cellsin accordance with EXPI293™ Expression System Kit (Life Technologies,A14635) protocols, and maintained for 4-6 days post transfection. Theamount of the exemplary trispecific proteins being tested, in theconditioned media, from the transfected EXPI293™ cells was quantitatedusing an Octet instrument with Protein A tips and using a controltrispecific protein for a standard curve.

T Cell Dependent Cellular Cytotoxicity Assays

Titrations of conditioned media was added to TDCC assays (T cellDependent Cell Cytotoxicity assays) to assess whether the anti-BCMAsingle domain antibody is capable of forming a synapse between T cellsand a BCMA-expressing cell line and direct the T cells to kill theBCMA-expressing cell line. In this assay (Nazarian et al., 2015. J.Biomol. Screen., 20:519-27), T cells and target cancer cell line cellswere mixed together at a 10:1 ratio in a 384-well plate, and varyingamounts of the trispecific proteins being tested were added. The tumorcell lines were engineered to express luciferase protein. After 48hours, to quantitate the remaining viable tumor cells, STEADY-GLO®Luminescent Assay (Promega) was used.

In this example EJM cells were used, which is a cell line that serves asan in vitro model for multiple myeloma and plasma cell leukemia.Viability of the EJM cells is measured after 48 hours. It was seen thatthe trispecific proteins mediated T cell killing. FIG. 2 shows anexample cell viability assay with test proteins 01H08, 01F07, 02F02 andBH253 compared to a negative control. The EC₅₀ for the TDCC activity ofseveral other test trispecific proteins are listed below in Table 1.

Binding Affinity

In the instant study, the binding affinity to human BCMA protein of theBCMA targeting trispecific proteins containing a BCMA binding proteinaccording to the present disclosure was determined. The affinitymeasurements are listed in Table 1.

TABLE 1 Binding affinity and TDCC Activity of several BCMA targetingtrispecific proteins. Construct Humanx BCMA KD TDCC EC50 Name (M) (M)253BH10 2.77E−08 5.29E−11 01H08 2.86E−09 3.41E−13 01F07 4.18E−097.02E−13 01H06 ND 1.00E−12 02G02 5.26E−09 1.08E−12 02B05 5.39E−091.22E−12 01C01 6.52E−09 1.33E−12 02F02 6.73E−09 1.36E−12 02E05 6.53E−091.37E−12 01E08 5.56E−09 1.50E−12 02C01 5.31E−09 1.55E−12 02E06 6.31E−091.57E−12 02B06 6.77E−09 1.65E−12 02F04 6.75E−09 1.72E−12 01G08 6.27E−091.91E−12 02C06 6.90E−09 1.95E−12 01H09 5.44E−09 2.21E−12 01F04 6.55E−092.21E−12 01D02 7.35E−09 2.25E−12 02D11 6.71E−09 2.35E−12 01A07 6.95E−092.49E−12 02C03 7.09E−09 2.52E−12 02F07 7.06E−09 2.59E−12 01E04 7.29E−092.67E−12 02H09 6.83E−09 2.88E−12 01E03 6.36E−09 2.98E−12 02F05 7.15E−093.00E−12 01B05 6.52E−09 3.01E−12 01C05 6.09E−09 3.07E−12 02F12 7.76E−093.14E−12 01H11 7.06E−09 3.17E−12 02G06 7.50E−09 3.39E−12 01E06 8.91E−093.77E−12 01G11 9.70E−09 3.98E−12 02A05 7.06E−09 4.21E−12 01A08 1.17E−084.25E−12 02G05 7.12E−09 4.33E−12 01B09 1.12E−08 5.27E−12 01G01 1.46E−085.83E−12 01B06 9.10E−09 6.97E−12 01F10 1.44E−08 7.44E−12 01E05 1.17E−081.08E−11 02G01 1.63E−08 1.08E−11 01A06 1.58E−08 1.10E−11 02B04 1.52E−081.13E−11 01D06 1.49E−08 1.35E−11 02B07 1.58E−08 1.42E−11 02B11 1.33E−081.44E−11 01H04 1.74E−08 1.47E−11 01D03 2.09E−08 1.49E−11 01A05 1.70E−081.51E−11 02F11 2.00E−08 1.52E−11 01D04 1.89E−08 1.60E−11 01B04 1.86E−081.61E−11 02C05 1.56E−08 1.62E−11 02E03 1.68E−08 1.65E−11 01D05 1.78E−081.66E−11 01C04 2.16E−08 1.75E−11 01E07 1.99E−08 1.92E−11 01G06 1.70E−081.92E−11 02F06 2.19E−08 1.93E−11 01B01 1.99E−08 1.95E−11 01D07 1.93E−081.96E−11 02A08 9.51E−09 2.01E−11 01A02 2.15E−08 2.18E−11 02G11 2.05E−082.38E−11 01G04 1.17E−08 2.41E−11 02F03 2.57E−08 2.45E−11 01C06 1.88E−082.51E−11 01A01 2.13E−08 2.64E−11 01B12 2.07E−08 2.73E−11 02A07 1.84E−082.79E−11 02G08 1.80E−08 2.86E−11 02E09 2.09E−08 3.11E−11 02H06 2.33E−083.19E−11 01H10 2.48E−08 3.52E−11 01F05 1.67E−08 3.72E−11 01C02 2.00E−083.73E−11 02A04 1.76E−08 3.82E−11 02H05 1.96E−08 3.89E−11 02G09 3.44E−083.96E−11 02D06 2.33E−08 4.28E−11 02G07 1.93E−08 4.46E−11 01H05 2.74E−084.54E−11 01C08 2.83E−08 4.57E−11 01A03 3.08E−08 4.61E−11 01A09 2.39E−084.84E−11 02B01 2.14E−08 5.18E−11 02H01 3.56E−08 5.42E−11 02H04 3.11E−085.99E−11 02A11 2.52E−08 6.06E−11 01E10 1.85E−08 6.23E−11 02D09 2.89E−086.73E−11 01F08 2.14E−08 7.12E−11 01F03 1.50E−08 7.64E−11 02H11 2.75E−087.75E−11 01C07 1.98E−08 8.33E−11 01B08 2.56E−08 8.76E−11 01B03 2.62E−089.64E−11 01H01 3.59E−08 1.18E−10 02B12 2.52E−08 1.24E−10 01G10 4.19E−081.43E−10 01A04 3.75E−08 1.59E−10 01B07 4.39E−08 1.74E−10 01C10 4.64E−082.08E−10 01F02 4.13E−08 2.25E−10 01B02 1.88E−08 3.59E−10 01F12 4.05E−083.92E−10 01G09 8.78E−08 4.41E−10 01D10 5.39E−08 4.53E−10 01F09 5.28E−089.45E−10 ND: Not determined.

Molecules 01H08, 01F07, 01H06, 02G02, 02B05, 01C01, 02F02, 02E05, 01E08,02C01, 02E06, 02B06, 02F04, 01G08, 02C06, 01H09, 01F04, 01D02, 02D11,01A07, 02CO3, 02F07, 01E04, 02H09, 01E03, 02F05, 01B05, 01C05, 02F12,01H11, 02G06, 01E06, 01G11, 02A05, 01A08, 02G05, 01B09, 01G01, 01B06,01F10, 01E05, 02G01, 01A06, 02B04, 01D06, 02B07, 02B11, 01H04, 01D03,01A05, 02F11, 01D04, 01B04, 02C05, 02E03, 01D05, 01C04, 01E07, 01G06,02F06, 01B01, 01D07, 02A08, 01A02, 02G11, 01G04, 02F03, 01C06, 01A01have at least two fold increase TDCC potency and also show increaseaffinity compared to a molecule with the parental CDRs, 253BH10.

Molecules 01H08, 01F07, 01H06, 02G02, 02B05, 01C01, 02F02, 02E05, 01E08,02C01, 02E06, 02B06, 02F04, 01G08, 02C06, 01H09, 01F04, 01D02, 02D11,01A07, 02CO3, 02F07, 01E04, 02H09, 01E03, 02F05, 01B05, 01C05, 02F12,01H11, 02G06, 01E06, 01G11, 02A05, 01A08, 02G05, 01B09 have at leastten-fold increase TDCC potency and also show increase affinity comparedto a molecule with the parental CDRs, 253BH10.

An anti-GFP trispecific molecule, included in these assays as a negativecontrol, had no detectable BCMA binding and no effect on cell viabilityin the TDCC assay (data not shown).

Example 2 Methods to Assess Binding and Cytotoxic Activities ofExemplary BCMA Targeting Trispecific Proteins According to the PresentDisclosure Against Jeko1, MOLP8 and OPM2 Cells

Protein Production

Sequences of BCMA targeting trispecific molecules, containing a BCMAbinding protein according to the present disclosure, preceded by aleader sequence and followed by a 6× Histidine Tag (SEQ ID NO: 471),were expressed using the vectors and methods previously described(Running Deer and Allison, 2004. Biotechnol Prog. 20:880-9) except lipidbased reagents and non-linearized plasmid DNA were used for celltransfection. Recombinant trispecific proteins were purified usingaffinity chromatography, ion exchange, and/or size exclusionchromatography. Purified protein was quantitated using theoreticalextinction coefficients and absorption spectroscopy. An image of aCoomassie stained SDS-PAGE demonstrates the purity of the proteins (FIG.3).

Cytotoxicity Assays

A human T-cell dependent cellular cytotoxicity (TDCC) assay was used tomeasure the ability of T cell engagers, including trispecific molecules,to direct T cells to kill tumor cells (Nazarian et al., 2015. J.,Biomol. Screen., 20:519-27). In this assay, T cells and target cancercell line cells are mixed together at a 10:1 ratio in a 384-well plate,and varying amounts of the trispecific proteins being tested are added.The tumor cell lines are engineered to express luciferase protein. After48 hours, to quantitate the remaining viable tumor cells, STEADY-GLO®Luminescent Assay (Promega) was used.

In the instant study, titrations of purified protein were added to TDCCassays (T cell Dependent Cell Cytotoxicity assays) to assess whether theanti-BCMA single domain antibody was capable of forming a synapsebetween T cells and BCMA-expressing Jeko1, MOLP8 and OPM2 cancer celllines. Jeko1 is a B cell lymphoma cell line. MOLP-8 is a myeloma cellline. OPM-2 is a human myeloma cell line.

Viability of the cells was measured after 48 hours. It was seen that thetrispecific proteins mediated T cell killing. FIG. 4 shows an examplecell viability assay with test proteins compared to a negative control.The EC₅₀ for the TDCC activity of several other test trispecificproteins are listed below in Table 2. An anti-GFP trispecific molecule,included in these assays as a negative control, had no effect on cellviability (data not shown).

TABLE 2 TDCC EC₅₀ Values for 3 Cell Lines for Select BCMA targetingtrispecific proteins in TriTAC ™ format (anti- target(BCMA):anti-albumin:anti-CD3 binding domains). Construct Jeko1 MOLP-8OPM-2 name EC50 (M) EC50 (M) EC50 (M) BH2T TriTAC ™ 3.2E−10 2.0E−101.6E−10 01F07 TriTAC ™ 5.3E−12 1.5E−12 4.4E−12 01F07-M34Y TriTAC ™5.6E−12 1.5E−12 3.6E−12 01F07-M34G TriTAC ™ 9.0E−12 2.2E−12 5.6E−1201G08 TriTAC ™ 1.5E−11 2.5E−12 6.9E−12 01H08 TriTAC ™ 4.0E−12 9.4E−133.1E−12 02B05 TriTAC ™ 8.3E−12 2.5E−12 6.5E−12 02B06 TriTAC ™ 1.1E−112.8E−12 9.7E−12 02E05 TriTAC ™ 1.1E−11 3.3E−12 1.2E−11 02E06 TriTAC ™9.1E−12 2.4E−12 7.4E−12 02F02 TriTAC ™ 8.2E−12 3.5E−12 1.0E−11 02F04TriTAC ™ 1.0E−11 2.5E−12 7.3E−12 02G02 TriTAC ™ 1.1E−11 2.8E−12 6.6E−1202G02-M34Y TriTAC ™ 1.1E−11 5.6E−12 6.2E−12 02G02-M34G TriTAC ™ 1.2E−114.0E−12 7.1E−12

Binding Affinity

In the instant study, the binding affinity to human BCMA protein of theBCMA targeting trispecific proteins containing a BCMA binding proteinaccording to the present disclosure was determined.

TABLE 3 Binding affinity of purified targeting trispecific proteinscontaining a BCMA binding protein according to the present disclosure.Construct name Human BCMA K_(D) (M) 01F07-M34Y TriTAC ™ 3.0E−0901F07-M34G TriTAC ™ 6.0E−09 02B05 TriTAC ™ 6.0E−09 02G02-M34Y TriTAC ™5.0E−09 02G02-M34G TriTAC ™ 7.0E−09

The data in FIG. 3, FIG. 4, Table 2 and Table 3 indicate the BCMAtargeting trispecific proteins can be expressed and purified to greaterthan 90% purity. The purified proteins exhibit about 13 fold to 213 foldmore potent TDCC activity compared to a trispecific protein with theparent BCMA targeting sequence. The purified trispecific proteins bindto BCMA with affinity of about 3 to 7 nM.

Example 3 Xenograft Tumor Model

An exemplary BCMA targeting trispecific protein described herein wasevaluated in a xenograft model.

On day 0, NCG mice were subcutaneously inoculated with RPMI-8226 cells,and also intraperitoneally implanted with normal human peripheral bloodmononuclear cells (PBMCs). Treatment with an exemplary BCMA targetingtrispecific protein (02B05) (SEQ ID NO: 520) was also started on day 0(qdx10) (once daily for 10 days). The dosage of administration was 5μg/kg, 50 μg/kg, or 500 μg/kg of the BCMA targeting trispecific protein02B05, or a vehicle as control. Tumor volumes were determined for 25days. As shown in FIG. 30, the mean tumor volumes were significantlylower in mice treated with the exemplary BCMA targeting trispecificprotein (02B05) (at 50 μg/kg, or 500 μg/kg), as compared to the micetreated with the vehicle or the lower dose of BCMA targeting trispecificprotein (02B05) (at 5 μg/kg).

On day 0, NCG mice were subcutaneously inoculated with Jeko 1 cells, andalso intraperitoneally implanted with normal human peripheral bloodmononuclear cells (PBMCs). Treatment with an exemplary BCMA targetingtrispecific protein (02B05) (SEQ ID NO: 520) was started on day 3(qdx10) (once daily for 10 days). The dosage of administration was 5μg/kg, 50 μg/kg, or 500 μg/kg of the BCMA targeting trispecific protein02B05, or a vehicle as control. Tumor volumes were determined for 25days. As shown in FIG. 31, the mean tumor volumes were significantlylower in mice treated with the exemplary BCMA targeting trispecificprotein (02B05) (at 500 μg/kg), as compared to the mice treated with thevehicle or the lower doses of BCMA targeting trispecific protein (02B05)(at 5 μg/kg or 50 μg/kg).

Example 4 Proof-of-Concept Clinical Trial Protocol for Administration ofa BCMA Trispecific Antigen-Binding Protein of this Disclosure MultipleMyeloma Patients

This is a Phase I/11 clinical trial for studying the BCMA trispecificantigen-binding protein of Example 1 as a treatment for MultipleMyeloma.

Study Outcomes:

Primary:

Maximum tolerated dose of BCMA targeting trispecific proteins of theprevious examples

Secondary:

To determine whether in vitro response of BCMA targeting trispecificproteins of is the previous examples are associated with clinicalresponse

Phase I

The maximum tolerated dose (MTD) will be determined in the phase Isection of the trial.

1.1 The maximum tolerated dose (MTD) will be determined in the phase Isection of the trial.

1.2 Patients who fulfill eligibility criteria will be entered into thetrial to BCMA targeting trispecific proteins of the previous examples.

1.3 The goal is to identify the highest dose of BCMA targetingtrispecific proteins of the previous examples that can be administeredsafely without severe or unmanageable side effects in participants. Thedose given will depend on the number of participants who have beenenrolled in the study prior and how well the dose was tolerated. Not allparticipants will receive the same dose.

Phase II

2.1 A subsequent phase II section will be treated at the MTD with a goalof determining if therapy with therapy of BCMA targeting trispecificproteins of the previous examples results in at least a 20% responserate.

Primary Outcome for the Phase II—To determine if therapy of BCMAtargeting trispecific proteins of the previous examples results in atleast 20% of patients achieving a clinical response (blast response,minor response, partial response, or complete response)

Eligibility

Eligibility criteria for inclusion in the studies are as follows:

-   -   Previously untreated patients with multiple myeloma and without        serious or imminent complications (e.g. impending pathologic        fracture, hypercalcemia, renal insufficiency). All asymptomatic        patients with low or intermediate tumor mass will qualify.

Patients with high tumor mass, symptomatic or impending fractures,hypercalcemia (corrected calcium >11.5 mg %), anemia (Hgb <8.5 gm/dl),renal failure (creatinine >2.0 mg/dl), high serum lactate dehydrogenase(>300 U/L) or plasma cell leukemia (>1000/ul) are ineligible.

Overt infections or unexplained fever should be resolved beforetreatment. Adequate liver function (including SGPT, bilirubin and LDH)is required.

Patients must have Zubrod performance of 1 or less.

Patients must provide written informed consent indicating that they areaware of the investigational nature of this study.

Life expectancy should exceed 1 year.

Patients with idiopathic monoclonal gammopathy and non-secretorymultiple myeloma are ineligible. Patients whose only prior therapy hasbeen with local radiotherapy, alpha-IFN, or ATRA are eligible. Patientsexposed to prior high-dose glucocorticoid or alkylating agent are noteligible.

Example 5 Affinity Measurements for Human and Cynomolgus BCMA, CD3ε, andAlbumin, Using an Exemplary BCMA Targeting Trispecific Protein of thisDisclosure

The aim of this study was to assess the affinity of an exemplary BCMAtargeting trispecific protein of this disclosure (02B05) (SEQ ID NO:520), toward human BCMA, cynomolgus BCMA, human CD3ε, cynomolgus CD3ε,human albumin, cynomolgus albumin, and mouse albumin. The affinitieswere measured using an Octet instrument. For these measurements,streptavidin tips were first loaded with 2.5 nM human BCMA-Fc, 2.5 nMcynomologus BCMA-Fc, 2.5 nM human CD3ε-Fc, 2.5 nM cynomolgus CD3ε-Fc, 50nM human serum albumin (HSA), 50 nM cynomolgus serum albumin, or 50 nMmouse serum albumin. Subsequently, the exemplary BCMA targetingtrispecific protein 02B05 was incubated with the tips, and following anassociation period, the tips were moved to a buffer solution to allowthe exemplary BCMA targeting trispecific protein (02B05) todisassociate. The affinities for binding to human and cynomolgus BCMAand CD3ε were measured in the presence of 15 mg/ml human serum albumin.Average calculated KD values from these studies are provided in Table 4(n indicates the number of independent measurements, n/d indicates nobinding detected under the conditions tested). Binding was detected tohuman BCMA, human CD3ε, cynomolgus CD3ε, human serum albumin, cynomolgusserum albumin, and mouse serum albumin. Under the conditions tested, nobinding was detected to cynomolgus BCMA.

TABLE 4 Measured K_(D) values for exemplary BCMA targeting trispecificprotein 02B05 to protein ligands. Protein ligand Species K_(D) (nM) nBCMA human 2.4 ± 0.2 2 cynomolgus n/d 2 CD3ε human 8 ± 1 2 cynomolgus7.8 ± 0.4 2 Albumin human 6 ± 1 3 cynomolgus 7.5 1 mouse 76   1

Example 6 Human T Cell Binding Ability of an Exemplary BCMA TargetingTrispecific Protein of this Disclosure

Exemplary BCMA targeting trispecific protein 02B05 (SEQ ID NO: 520) wastested for its ability to bind to purified T cells. Briefly, the BCMAtrispecific protein or phosphate buffered saline (PBS) were incubatedwith purified T cells from 4 different anonymous human donors. Afterwashing unbound protein, the T cells were then incubated with an AlexaFluor 647 conjugated antibody that recognizes the anti-albumin domain inthe 02B05 BCMA trispecific antigen-binding protein. The T cells werethen analyzed by flow cytometry. It was observed that human T cellsincubated with the 02B05 BCMA trispecific antigen-binding protein hadnotable shifts associated with Alexa Fluor 647 staining compared tocells that were incubated with PBS. The results are shown in FIGS. 5A,5B, 5C, and 5D. In conclusion, this study indicated that the exemplaryBCMA targeting trispecific protein was able to bind human T cells.

Example 7 Ability of an Exemplary BCMA Targeting Trispecific Protein ofthis Disclosure to Bind BCMA Expressing Cells

Exemplary BCMA targeting trispecific protein 02B05 (SEQ ID NO: 520) wastested for its ability to bind to BCMA expressing cells. Briefly, the02B05 BCMA trispecific antigen-binding protein was incubated with celllines expressing BCMA (NCI-H929; EJM; RPMI-8226; OPM2) or lacking BCMA(NCI-H510A; DMS-153). Expression of BCMA RNA in these cells is indicatedby the FPKM (fragments per kilobase million) values listed in FIGS.6A-F: the RNA FPKM values are from the Cancer Cell Line Encyclopedia(Broad Institute, Cambridge, Mass. USA). After washing unbound protein,the cells were then incubated with an Alexa Fluor 647 conjugatedantibody that recognizes the anti-albumin domain in the 02B05 BCMAtrispecific antigen-binding protein. The cells were then analyzed byflow cytometry. As a negative control, cells were incubated with atrispecific protein targeting GFP. Cells expressing BCMA RNA andincubated with the BCMA trispecific protein had notable shiftsassociated with Alexa Fluor 647 staining compared to cells that wereincubated with GFP trispecific protein (as in FIGS. 6A, 6B, 6D, and 6E).Whereas, cells lacking BCMA RNA produced equivalent Alexa Fluor 647staining with the BCMA trispecific protein and the GFP trispecificprotein (as seen in FIGS. 6C, and 6F). Thus, this study indicated thatthe exemplary BCMA trispecific antigen-binding was able to selectivelybind to cells expressing BCMA.

Example 8 Ability of an Exemplary BCMA Targeting Trispecific Protein toMediate T Cell Killing of Cancer Cells Expressing BCMA

Exemplary BCMA trispecific protein 02B05 (SEQ ID NO: 520) was tested forits ability to direct T cells to kill BCMA expressing cells in thepresence and absence of human serum albumin (HSA) using a standard TDCCassay as described in Example 1. Because the exemplary BCMA trispecificprotein contains an anti-albumin domain, this experiment was performedto confirm that binding to albumin would not prevent the BCMAtrispecific antigen-binding protein from directing T cells to kill BCMAexpressing cells. Five BCMA expressing cell lines were tested: EJM,Jeko, OPM2, MOLP8, and NCI-H929. Representative data for an experimentwith the EJM cells are shown in FIG. 7. It was observed that viabilityof the EJM cells decreased with increasing amount of the exemplary 02B05BCMA trispecific antigen-binding protein in the presence or absence ofhuman serum albumin (HSA), whereas a control GFP targeting trispecificprotein did not affect cell viability. In the presence of albumin,higher concentrations of BCMA trispecific protein were needed to reduceviability of the EJM cells. The EC₅₀ values for cell killing by BCMAtrispecific protein for the EJM cells as well as the Jeko, OPM2, MOLE,and NCI-H929 cells in the absence or presence of HSA are provided inTable 5. With all five cell lines, the exemplary 02B05 BCMA trispecificantigen-binding protein directed T cells to kill target cells in thepresence of HSA.

TABLE 5 TDCC EC₅₀ Values for an exemplary BCMA targeting trispecificprotein in the presence or absence of human serum albumin with fivedifferent BCMA expressing cell lines EC₅₀ without HSA EC₅₀ with HSA CellLine (pM) (pM) EJM 1.0 53 Jeko 8.3 662 OPM2 6.5 328 MOLP8 2.5 388NCI-H929 6.7 194

Example 9 Ability of an Exemplary BCMA Targeting Trispecific Protein toMediate T Cell Killing of Cancer Cells Expressing BCMA, Using a SmallerTarget Cell to Effector Cell Ratio

In the standard TDCC assay (as described in Example 1), a ratio 1 targetcell (EJM cells or OPM2 cells) per 10 effector cells (T cells) is usedin a 48 hour assay. In this experiment, the ability of exemplary BCMAtrispecific protein 02B05 (SEQ ID NO: 520) to direct T cells to killtarget cells with smaller target cell to effector ratios was tested. Theexpectation was that less killing would be observed when fewer effectorcells were used. Two BCMA expressing cell lines were tested, EJM andOPM2, using target to effector cell ratios of 1:1, 1:3, and 1:10, andthe experiment was performed in the presence of 15 mg/ml HSA. A GFPtargeting trispecific protein was used as a negative control. Data fromthis experiment is shown in FIG. 8 (TDCC assay with EJM cells) and FIG.9 (TDCC assay with OPM2 cells). As expected, near complete killing ofthe target cells was observed with a 1:10 target to effector cell ratio.The amount of killing was reduced with decreasing effector cells. TheEC₅₀ values for cell killing with each ratio are listed in Table 6 (n/dindicates insufficient killing was observed to calculate an EC₅₀ value).The EC₅₀ values increased when fewer effector cells were present. Thus,as expected, reducing the number of effector cells to target cellsreduced TDCC activity of the BCMA trispecific protein.

TABLE 6 TDCC EC₅₀ values for an exemplary BCMA targeting trispecificprotein (02B05) with varied target cell (EJM cells) to effector cell (Tcells) ratios (tested in presence of 15 mg/ml HSA) Target cell:T CellEJM EC₅₀ OPM2 EC₅₀ ratio (pM) (pM)  1:10 154 371 1:3 523 1896 1:1 1147n/d

Example 10 Ability of an Exemplary BCMA Targeting Trispecific Protein toMediate T Cell Killing of Cancer Cells Expressing BCMA, in a Time CourseStudy, Using a Smaller Target Cell to Effector Cell Ratio

In the standard TDCC assay (Example 1), a ratio 1 target cell per 10effector cells (T cells) is used in a 48 hour assay. In this experiment,a time course was performed using a 1 to 1 ratio of target cells (EJMcells) to effector cells (T cells). The expectation was that withincreased time, a 1 to 1 ratio would result in target cell killing. Theexperiment was performed in the presence of 15 mg/ml HSA. A GFPtargeting trispecific protein was used as a negative control. Targetcell viability was measured on days 1, 2, 3, and 4 following incubationof the target cells and effector cells, at a 1:1 ratio, in presence ofthe exemplary 02B05 BCMA trispecific antigen-binding protein and 15mg/ml HSA, or the GFP targeting trispecific protein and 15 mg/ml HSA.While no target cell killing was observed on day 1, killing was observedat all other time points in the presence of the BCMA trispecificantigen-binding protein, with the amount of killing increasing with time(FIG. 10). Killing with not observed with the GFP targeting trispecificprotein. The EC₅₀ values calculated for cell killing on each day areprovided in Table 7 (n/d indicates insufficient killing to determine anEC₅₀ value). From this study it was concluded that the exemplary 02B05BCMA trispecific protein was able to direct T cell killing with lowernumbers of effector cells, but more time was needed to achieve morecomplete killing.

TABLE 7 TDCC EC₅₀ values for an exemplary BCMA targeting trispecificprotein (02B05) with a 1to 1 target cell (EJM cells) to effector cell (Tcells) ratios (tested in presence of 15 mg/ml HSA), at varied timepoints EC₅₀ (pM) Day 1 n/d Day 2 1859 Day 3 1420 Day 4 1012

Example 11 Ability of an Exemplary BCMA Targeting Trispecific Protein toDirect Human T Cells to Kill BCMA Expressing Cells

Exemplary BCMA trispecific protein 02B05 (SEQ ID NO: 520) was tested forits ability to direct T cells from four different anonymous human donorsto kill four different BCMA expressing cells in the presence of 15 mg/mlhuman serum albumin (HSA) using a standard TDCC assay as described inExample 1. The BCMA expressing cell lines were EJM, NCI-H929, OPM2, andRPMI8226. As negative controls, two cell lines that lack BCMAexpression, OVCAR8 and NCI-H510A, were also tested in the TDCC assays. Acontrol GFP targeting trispecific protein was also used as a negativecontrol. With the four BCMA expressing cell lines and all four T celldonors, cell viability decreased with increasing amounts of the BCMAtrispecific protein but not with the GFP trispecific protein (FIGS. 11,12, 13, and 14). The EC₅₀ values for cell killing are provided in Table8. The exemplary 02B05 BCMA trispecific antigen-binding protein did notdirect killing of the cell lines lacking BCMA expression (FIGS. 15 and16). Thus, it was inferred that the exemplary 02B05 BCMA trispecificantigen-binding protein was able to direct T cells from multiple donorsto kill a spectrum of BCMA expressing cell lines.

TABLE 8 Exemplary 02B05 BCMA trispecific protein EC₅₀ values from TDCCassays with four BCMA expressing cell lines and four T cell donors inpresence of 15 mg/ml HSA EC₅₀ (pM) H929 OPM2 RPMI8226 EJM Donor 02 169250 275 151 Donor 35 113 199 371 121 Donor 81 124 265 211 143 Donor 86239 416 543 191

Example 12 Ability of an Exemplary BCMA Targeting Trispecific Protein toDirect Cynomolgus T Cells to Kill BCMA Expressing Cells

Exemplary BCMA targeting trispecific protein 02B05 (SEQ ID NO: 520) wastested for its ability to direct T cells from cynomolgus monkeys to killBCMA expressing cells in the presence of 15 mg/ml human serum albumin(HSA). The experimental conditions were the same as described in Example1 except peripheral blood mononuclear cells (PBMC) from cynomolgusmonkeys were used as a source of T cells. Two BCMA expressing cell lineswere tested, RPMI8226 and NCI-H929. As shown in FIGS. 17 and 18, theBCMA trispecific protein was able to direct T cells present in thecynomolgus PBMCs to kill the two BCMA expressing cell lines. The EC₅₀values for the cell killing are listed in Table 9. A GFP trispecificprotein did not affect viability of the BCMA expressing cells. Thus, theBCMA expressing trispecific protein, which can bind cynomolgus CD3ε (asshown in Example 5), can direct cynomolgus T cells to kill cellsexpressing human BCMA.

TABLE 9 BCMA trispecific protein EC₅₀ values from TDCC Assays with twocell lines and two cynomolgusy PMBC donors in the presence of 15 mg/mlHSA EC₅₀ (pM) RPMI8226 NCI-H929 Donor G322 3654 1258 Donor GA33 1003 288

Example 13 Exemplary BCMA Trispecifc Antigen-Binding Protein and TargetTumor Cell-Mediated Induction of T Cell Activation

Exemplary BCMA targeting trispecific protein 02B05 (SEQ ID NO: 520) wastested for its ability to activate T cells in the presence of BCMAexpressing cells. The BCMA expressing cell lines were EJM, OPM2, andRPMI8226. As negative controls, two cells lines that lack BCMAexpression were also included, OVCAR8 and NCI-H510A. T cells wereobtained from four different anonymous human donors. The assays were setup using the conditions of a standard TDCC assay as described in Example1 except the assay was adapted to 96 well format and the assay wascarried out in the presence of 15 mg/ml HSA. After the 48 hour assay, Tcell activation was assessed by using flow cytometry to measureexpression of T cell activation biomarkers CD25 and CD69 on the surfaceof the T cells. With increasing concentrations of the exemplary 02B05BCMA trispecific antigen-binding protein increased expression of CD69and CD25 was observed on T cells when co-cultured with the BCMAexpressing cells (as shown in FIGS. 19-24). Thus, the observed increasedexpression was dependent on interaction of the BCMA binding sequencewithin the exemplary 02B05 BCMA trispecific antigen-binding protein withBCMA, as little to no activation was observed with a control GFPtrispecific protein (as shown in FIGS. 19-24) or with target cells withno BCMA expression (as shown in FIGS. 25-28). Therefore the exemplary02B05 BCMA trispecific antigen-binding protein activated T cells inco-cultures containing BCMA expressing cells. This conclusion isbolstered by additional data. For instance, expression of a cytokine,TNFα, was measured in the medium collected from a co-culture of T cellsand BCMA expressing target cells treated with increasing concentrationsof the exemplary 02B05 BCMA trispecific antigen-binding protein or withthe negative control GFP trispecific protein. The co-cultures were setup using the conditions of a standard TDCC assay (as described inExample 1) supplemented with 15 mg/ml HSA. TNFα was measured using anelectrochemiluminescent assay (Meso Scale Discovery). Robust inductionof TNFα expression was observed with the 02B05 exemplary BCMA targetingtrispecific protein and not the GFP trispecific protein (FIG. 29). Thisresult further supports that the 02B05 exemplary BCMA targetingtrispecific protein activated T cells in co-cultures containing BCMAexpressing cells.

Example 14 Pharmacokinetics of an Exemplary BCMA Targeting TrispecificProtein of this Disclosure

Cynomolgus monkeys were administered single intravenous doses of anexemplary BCMA targeting trispecific protein (02B05) (SEQ ID NO: 520),at 0.01 mg/kg, 0.1 mg/kg, or 1 mg/kg. Two animals were included per dosegroup. Following the administration, serum samples were collected andanalyzed by two different electrochemiluminescent assays. One assay usedbiotinylated CD3ε as a capture reagent and detected with sulfo taggedBCMA (termed the functional assay). Another assay used as a capturereagent a biotinylated antibody recognizing the anti-albumin domain inthe exemplary BCMA targeting trispecific protein and used as a detectionreagent a sulfo tagged antibody recognizing the anti-CD3 binding domainin the exemplary BCMA targeting trispecific protein (i.e., ananti-idiotype antibody). The results from the electrochemiluminescentassays are plotted in FIG. 32. As seen in FIG. 32, the exemplary BCMAtargeting trispecific protein was detected in the cynomolgus serumsamples, even after 504 hours after the administration. The exemplaryBCMA targeting trispecific protein was identified using both thesulfo-tagged BCMA (lines labeled using the term “functional” in FIG. 32)and by the anti-idiotype antibody (lines labeled using the term“anti-idiotype” in FIG. 32).

To confirm that the exemplary BCMA targeting trispecific proteinretained the ability to direct T cells to kill BCMA expressing EJMcells, after in vivo administration, serum samples from the 168 hourtime point were tested in a TDCC assay (as described in Example 1) inthe presence of 16.7% serum from a cynomolgus monkey that has not beenexposed to a BCMA targeting trispecific protein, titrating the exemplaryBCMA targeting trispecific protein using the protein concentrationsdetermined using the electrochemiluminescent assays (shown in FIG. 33).Fresh diluted exemplary 02B05 BCMA trispecific protein was compared tothe BCMA trispecific protein collected from the test cynomolgus monkeysat 168 h. A GFP trispecific protein was included as a negative control.This study demonstrated that the exemplary BCMA targeting trispecificprotein collected from the test cynomolgus monkeys' serum had identicalactivity as freshly diluted protein, and that the protein in the serumsamples retained the ability to direct T cells to kill BCMA expressingtarget cells.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

Sequence Table SEQ ID NO: Description Sequence 1. Exemplary CDR1X₁X₂X₃X₄X₅X₆X₇PX₈G where X₁ is T or S; X₂ is N, D, or S;X₃ is I, D, Q, H, V, or E; X₄ is F, S, E, A, T, M, V,I, D, Q, P, R, or G; X₅ is S, M, R, or N; X₆ is I, K,S, T, R, E, D, N, V, H, L, A, Q, or G; X₇ is S, T, Y,R, or N; and X₈ is M, G, or Y 2. Exemplary CDR2AIX₉GX₁₀X₁₁TX₁₂YADSVK where X₉ is H, N, or S; X₁₀ is F,G, K, R, P, D, Q, H, E, N, T, S, A, I, L, or V; X₁₁is S, Q, E, T, K, or D; and X₁₂ is L, V, I, F, Y, or W 3. Exemplary CDR3VPWGX₁₃YHPX₁₄X₁₅VX₁₆ where X₁₃ is D, I, T, K, R, A, E,S, or Y; X₁₄ is R, G, L, K, T, Q, S, or N; X₁₅ is N,K, E, V, R, M, or D; and X₁₆ is Y, A, V, K, H, L, M, T, R, Q, C, S, or NSEQ ID NO: Name HCDR1   4. 01A01 TDIFSISPMG   5. 01A02 TNIFSSSPMG   6.01A03 TNIFSISPGG   7. 01A04 TNIFMISPMG   8. 01A05 TNIFSSSPMG   9. 01A06TNIFSIRPMG  10. 01A07 TNISSISPMG  11. 01A08 TNIFSSSPMG  12. 01A09TNIFSITPMG  13. 01B01 TNIPSISPMG  14. 01B02 TNITSISPMG  15. 01B03TNIFSKSPMG  16. 01B04 TNDFSISPMG  17. 01B05 TNITSISPMG  18. 01B06TNIFSISPMG  19. 01B07 TNIFSRSPMG  20. 01B08 TNIESISPMG  21. 01B09SNIFSISPMG  22. 01B12 TNIFSTSPMG  23. 01C01 TNIVSISPMG  24. 01C02TNIESISPMG  25. 01C04 TNIPSISPMG  26. 01C05 TNIFSSSPMG  27. 01C06TNIFSISPMG  28. 01C07 TNIFSIYPMG  29. 01C08 TNIFSNSPMG  30. 01C10TNISSISPMG  31. 01D02 TNIVSISPMG  32. 01D03 TNIFSNSPMG  33. 01D04TNITSISPMG  34. 01D05 TNIFSDSPMG  35. 01D06 TNIFSRSPMG  36. 01D07TNIFSASPMG  37. 01D10 TNIFSASPMG  38. 01E03 TNITSISPMG  39. 01E04TNIASISPMG  40. 01E05 TNIFSRSPMG  41. 01E06 TNIFSLSPMG  42. 01E07TNIPSISPMG  43. 01E08 TNIFSQSPMG  44. 01E10 TNIESISPMG  45. 01F02TNIFSHSPMG  46. 01F03 TNIFSESPMG  47. 01F04 TNIDSISPMG  48. 01F05TNIFSSSPMG  49. 01F07 TNIFSTSPMG  50. 01F08 TNITSVSPMG  51. 01F09TNISSISPMG  52. 01F10 SNIFSISPMG  53. 01F12 TNIFRISPMG  54. 01G01TNIVSISPMG  55. 01G04 TNIDSISPMG  56. 01G06 TNIFSRSPMG  57. 01G08TNIQSISPMG  58. 01G09 TNIFNISPMG  59. 01G10 TNEFSISPMG  60. 01G11TNIPSISPMG  61. 01H01 TNIGSISPMG  62. 01H04 TNIFSKSPMG  63. 01H05TNIFSITPMG  64. 01H06 TSDFSISPMG  65. 01H08 TNIMSISPMG  66. 01H09TNIMSISPMG  67. 01H10 TNIPSISPMG  68. 01H11 TNIFSTSPMG  69. 02A04TNIFSQSPMG  70. 02A05 TNIASISPMG  71. 02A07 TNIFSKSPMG  72. 02A08TNIFSRSPMG  73. 02A11 TNHFSISPMG  74. 02B01 TNIFSNSPMG  75. 02B04TNIFSTSPMG  76. 02B05 TNIFSISPYG  77. 02B06 TNIFSNSPMG  78. 02B07TNIFSSSPMG  79. 02B11 TNIVSISPMG  80. 02B12 TNISSISPMG  81. 02C01TNIISISPMG  82. 02C03 TNIASISPMG  83. 02C05 TNIFSESPMG  84. 02C06TNIFSTSPMG  85. 02D06 TNISSISPMG  86. 02D09 TNVVSISPMG  87. 02D11TNEFSISPMG  88. 02E03 TNIFSNSPMG  89. 02E05 TNIFSRSPMG  90. 02E06TNIFSDSPMG  91. 02E09 TNDFSISPMG  92. 02F02 TNIFSKSPMG  93. 02F03TNIFSIYPMG  94. 02F04 TNIFSSSPMG  95. 02F05 TNIFSVSPMG  96. 02F06TNIFSITPMG  97. 02F07 TNIESISPMG  98. 02F11 TNIFSTSPMG  99. 02F12TNIESISPMG 100. 02G01 TNIFSINPMG 101. 02G02 TNIFSITPMG 102. 02G05TNITSISPMG 103. 02G06 TNIFSGSPMG 104. 02G07 TNIFSITPMG 105. 02G08TNIDSISPMG 106. 02G09 TNIFSDSPMG 107. 02G11 TNIDSISPMG 108. 02H01TNIFSKSPMG 109. 02H04 TNIFSVSPMG 110. 02H05 TNQFSISPMG 111. 02H06TNIRSISPMG 112. 02H09 TNIFSRSPMG 113. 02H11 TNITSISPMG 114. 01F07-M34YTNIFSTSPYG 115. 01F01-M34G TNIFSTSPGG 116. 02G02-M34Y TNIFSITPYG 117.02G02-M34G TNIFSITPGG Name CDR2 118. 01A01 AIHGGSTLYADSVK 119. 01A02AINGFSTLYADSVK 120. 01A03 AIHGSSTLYADSVK 121. 01A04 AIHGDSTLYADSVK 122.01A05 AIHGESTLYADSVK 123. 01A06 AIHGESTVYADSVK 124. 01A07 AIHGTSTLYADSVK125. 01A08 AIHGESTLYADSVK 126. 01A09 AIHGRSTLYADSVK 127. 01B01AIHGESTLYADSVK 128. 01B02 AISGFSTLYADSVK 129. 01B03 AIHGKSTLYADSVK 130.01B04 AIHGKSTLYADSVK 131. 01B05 AIHGFETLYADSVK 132. 01B06 AIHGDSTLYADSVK133. 01B07 AIHGNSTLYADSVK 134. 01B08 AIHGSSTLYADSVK 135. 01B09AIHGSSTLYADSVK 136. 01B12 AIHGFQTLYADSVK 137. 01C01 AIHGHSTLYADSVK 138.01C02 AIHGNSTLYADSVK 139. 01C04 AIHGDSTLYADSVK 140. 01C05 AIHGEKTLYADSVK141. 01C06 AIHGDSTLYADSVK 142. 01C07 AIHGESTYYADSVK 143. 01C08AIHGGSTLYADSVK 144. 01C10 AIHGESTLYADSVK 145. 01D02 AIHGKSTLYADSVK 146.01D03 AIHGDSTLYADSVK 147. 01D04 AIHGVSTLYADSVK 148. 01D05 AIHGTSTLYADSVK149. 01D06 AIHGDSTLYADSVK 150. 01D07 AIHGSSTLYADSVK 151. 01D10AIHGSSTLYADSVK 152. 01E03 AIHGDSTLYADSVK 153. 01E04 AIHGTSTLYADSVK 154.01E05 AIHGTSTLYADSVK 155. 01E06 AIHGDSTLYADSVK 156. 01E07 AIHGQSTLYADSVK157. 01E08 AIHGDSTLYADSVK 158. 01E10 AIHGKSTLYADSVK 159. 01E02AIHGTSTLYADSVK 160. 01F03 AIHGNSTLYADSVK 161. 01F04 AIHGFQTLYADSVK 162.01F05 AIHGFSTWYADSVK 163. 01F07 AIHGFSTIYADSVK 164. 01F08 AIHGPSTLYADSVK165. 01F09 AIHGHSTLYADSVK 166. 01F10 AIHGESTLYADSVK 167. 01F12AIHGDSTLYADSVK 168. 01G01 AIHGDSTLYADSVK 169. 01G04 AIHGNSTLYADSVK 170.01G06 AIHGFETLYADSVK 171. 01G08 AIHGFETLYADSVK 172. 01G09 AIHGFSTYYADSVK173. 01G10 AIHGLSTLYADSVK 174. 01G11 AIHGASTLYADSVK 175. 01H01AIHGQSTLYADSVK 176. 01H04 AIHGQSTLYADSVK 177. 01H05 AIHGTSTLYADSVK 178.01H06 AIHGFETLYADSVK 179. 01H08 AIHGFSTVYADSVK 180. 01H09 AIHGNSTLYADSVK181. 01H10 AIHGESTLYADSVK 182. 01H11 AIHGFSTLYADSVK 183. 02A04AIHGKSTLYADSVK 184. 02A05 AIHGKSTLYADSVK 185. 02A07 AIHGNSTLYADSVK 186.02A08 AIHGESTLYADSVK 187. 02A11 AIHGSSTLYADSVK 188. 02B01 AIHGRSTLYADSVK189. 02B04 AIHGFSTIYADSVK 190. 02B05 AIHGTSTLYADSVK 191. 02B06AIHGFSTLYADSVK 192. 02B07 AIHGHSTLYADSVK 193. 02B11 AIHGDSTLYADSVK 194.02B12 AIHGFDTLYADSVK 195. 02C01 AIHGASTLYADSVK 196. 02C03 AIHGSSTLYADSVK197. 02C05 AIHGFTTLYADSVK 198. 02C06 AIHGTSTLYADSVK 199. 02D06AIHGFSTVYADSVK 200. 02D09 AIHGKSTLYADSVK 201. 02D11 AIHGESTLYADSVK 202.02E03 AIHGPSTLYADSVK 203. 02E05 AIHGISTLYADSVK 204. 02E06 AIHGFSTFYADSVK205. 02E09 AIHGGSTLYADSVK 206. 02F02 AIHGSSTLYADSVK 207. 02F03AIHGSSTLYADSVK 208. 02F04 AIHGFSTLYADSVK 209. 02F05 AIHGNSTLYADSVK 210.02F06 AIHGESTLYADSVK 211. 02F07 AIHGFSTLYADSVK 212. 02F11 AIHGTSTLYADSVK213. 02F12 AIHGTSTLYADSVK 214. 02G01 AIHGFDTLYADSVK 215. 02G02AIHGASTLYADSVK 216. 02G05 AIHGNSTLYADSVK 217. 02G06 AIHGNSTLYADSVK 218.02G07 AIHGESTLYADSVK 219. 02G08 AIHGESTLYADSVK 220. 02G09 AIHGFSTLYADSVK221. 02G11 AIHGSSTLYADSVK 222. 02H01 AIHGSSTLYADSVK 223. 02H04AIHGNSTLYADSVK 224. 02H05 AIHGKSTLYADSVK 225. 02H06 AIHGSSTLYADSVK 226.02H09 AIHGSSTLYADSVK 227. 02H11 AIHGESTLYADSVK 228. 01F07-M34YAIHGFSTIYADSVK 229. 01F01-M34G AIHGFSTIYADSVK 230. 02G02-M34YAIHGASTLYADSVK 231. 02G02-M34G AIHGASTLYADSVK Name CDR3 232. 01A01VPWGDYHPRNVA 233. 01A02 VPWGDYHPRNVH 234. 01A03 VPWGDYHPRNVY 235. 01A04VPWGRYHPRNVY 236. 01A05 VPWGDYHPRNVY 237. 01A06 VPWGDYHPRNVY 238. 01A07VPWGDYHPGNVY 239. 01A08 VPWGDYHPRKVY 240. 01A09 VPWGSYHPRNVY 241. 01B01VPWGDYHPRNVA 242. 01B02 VPWGDYHPRNVY 243. 01B03 VPWGDYHPRNVV 244. 01B04VPWGDYHPRNVK 245. 01B05 VPWGDYHPGNVY 246. 01B06 VPWGEYHPRNVY 247. 01B07VPWGIYHPRNVY 248. 01B08 VPWGRYHPRNVY 249. 01B09 VPWGDYHPGNVY 250. 01B12VPWGDYHPRNVV 251. 01C01 VPWGDYHPGNVY 252. 01C02 VPWGRYHPRNVY 253. 01C04VPWGDYHPRNVY 254. 01C05 VPWGDYHPGNVY 255. 01C06 VPWGKYHPRNVY 256. 01C07VPWGSYHPRNVY 257. 01C08 VPWGDYHPRNVH 258. 01C10 VPWGYYHPRNVY 259. 01D02VPWGDYHPGNVY 260. 01D03 VPWGDYHPRNVR 261. 01D04 VPWGDYHPRNVQ 262. 01D05VPWGDYHPRNVY 263. 01D06 VPWGDYHPRNVT 264. 01D07 VPWGDYHPRNVN 265. 01D10VPWGRYHPRNVY 266. 01E03 VPWGDYHPGNVY 267. 01E04 VPWGDYHPGNVY 268. 01E05VPWGKYHPRNVY 269. 01E06 VPWGDYHPRNVY 270. 01E07 VPWGDYHPRNVQ 271. 01E08VPWGDYHPGNVC 272. 01E10 VPWGDYHPRRVY 273. 01F02 VPWGRYHPRNVY 274. 01F03VPWGTYHPRNVY 275. 01F04 VPWGDYHPGNVY 276. 01F05 VPWGRYHPRNVY 277. 01F07VPWGDYHPGNVY 278. 01F08 VPWGDYHPTNVY 279. 01F09 VPWGRYHPRNVY 280. 01F10VPWGDYHPRNVT 281. 01F12 VPWGRYHPRNVY 282. 01G01 VPWGDYHPRRVY 283. 01G04VPWGDYHPRNVY 284. 01G06 VPWGDYHPRNVL 285. 01G08 VPWGDYHPGNVY 286. 01G09VPWGRYHPRNVY 287. 01G10 VPWGAYHPRNVY 288. 01G11 VPWGDYHPRNVA 289. 01H01VPWGDYHPQNVY 290. 01H04 VPWGDYHPRNVT 291. 01H05 VPWGRYHPRNVY 292. 01H06VPWGDYHPGNVY 293. 01H08 VPWGDYHPGNVY 294. 01H09 VPWGDYHPGNVY 295. 01H10VPWGDYHPRNVY 296. 01H11 VPWGDYHPGNVY 297. 02A04 VPWGDYHPSNVY 298. 02A05VPWGDYHPGNVY 299. 02A07 VPWGDYHPREVY 300. 02A08 VPWGRYHPGNVY 301. 02A11VPWGDYHPRVVY 302. 02B01 VPWGDYHPRNVM 303. 02B04 VPWGDYHPLNVY 304. 02B05VPWGDYHPGNVY 305. 02B06 VPWGDYHPGNVY 306. 02B07 VPWGDYHPRNVT 307. 02B11VPWGDYHPRNVS 308. 02B12 VPWGDYHPRNVY 309. 02C01 VPWGDYHPGNVY 310. 02C03VPWGDYHPGNVY 311. 02C05 VPWGDYHPRNVT 312. 02C06 VPWGDYHPGNVY 313. 02D06VPWGRYHPRNVY 314. 02D09 VPWGDYHPNNVY 315. 02D11 VPWGDYHPGNVY 316. 02E03VPWGDYHPRNVT 317. 02E05 VPWGDYHPGNVY 318. 02E06 VPWGDYHPGNVY 319. 02E09VPWGDYHPRNVA 320. 02F02 VPWGDYHPGNVY 321. 02F03 VPWGDYHPKNVY 322. 02F04VPWGDYHPGNVY 323. 02F05 VPWGKYHPRNVY 324. 02F06 VPWGRYHPRNVY 325. 02F07VPWGDYHPGNVY 326. 02F11 VPWGDYHPRNVQ 327. 02F12 VPWGDYHPGNVY 328. 02G01VPWGDYHPRNVS 329. 02G02 VPWGDYHPGNVY 330. 02G05 VPWGDYHPGNVY 331. 02G06VPWGDYHPGNVY 332. 02G07 VPWGDYHPRDVY 333. 02G08 VPWGDYHPRNVT 334. 02G09VPWGDYHPRNVA 335. 02G11 VPWGDYHPRNVT 336. 02H01 VPWGDYHPRNVY 337. 02H04VPWGDYHPRNVY 338. 02H05 VPWGDYHPRNVV 339. 02H06 VPWGDYHPRNVV 340. 02H09VPWGDYHPGNVY 341. 02H11 VPWGDYHPRNVY 342. 01F07-M34Y VPWGDYHPGNVY 343.01F01-M34G VPWGDYHPGNVY 344. 02G02-M34Y VPWGDYHPGNVY 345. 02G02-M34GVPWGDYHPGNVY SEQ Construct ID NO Name VHH Sequences 346. BH2TEVQLVESGGGLVQPGRSLTLSCAASTNIFSISPMGWYRQAPGKQRELVAAIHGFSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VYWGQGTQVTVSS 347.01A01 EVQLVESGGGLVQPGRSLTLSCAASTDIFSISPMGWYRQAPGKQRELVAAIHGGSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VAWGQGTQVTVSS 348.02E09 EVQLVESGGGLVQPGRSLTLSCAASTNDFSISPMGWYRQAPGKQRELVAAIHGGSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VAWGQGTQVTVSS 349.01B03 EVQLVESGGGLVQPGRSLTLSCAASTNIFSKSPMGWYRQAPGKQRELVAAIHGKSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VVWGQGTQVTVSS 350.01B04 EVQLVESGGGLVQPGRSLTLSCAASTNDFSISPMGWYRQAPGKQRELVAAIHGKSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VKWGQGTQVTVSS 351.02H05 EVQLVESGGGLVQPGRSLTLSCAASTNQFSISPMGWYRQAPGKQRELVAAIHGKSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VVWGQGTQVTVSS 352.01A02 EVQLVESGGGLVQPGRSLTLSCAASTNIFSSSPMGWYRQAPGKQRELVAAINGFSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VHWGQGTQVTVSS 353.01A05 EVQLVESGGGLVQPGRSLTLSCAASTNIFSSSPMGWYRQAPGKQRELVAAIHGFSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VYWGQGTQVTVSS 354.01B12 EVQLVESGGGLVQPGRSLTLSCAASTNIFSTSPMGWYRQAPGKQRELVAAIHGFQTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VVWGQGTQVTVSS 355.01G06 EVQLVESGGGLVQPGRSLTLSCAASTNIFSRSPMGWYRQAPGKQRELVAAIHGFETLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VLWGQGTQVTVSS 356.02C05 EVQLVESGGGLVQPGRSLTLSCAASTNIFSESPMGWYRQAPGKQRELVAAIHGFTTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VTWGQGTQVTVSS 357.02G09 EVQLVESGGGLVQPGRSLTLSCAASTNIFSDSPMGWYRQAPGKQRELVAAIHGFSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VAWGQGTQVTVSS 358.01C08 EVQLVESGGGLVQPGRSLTLSCAASTNIESNSPMGWYRQAPGKQRELVAAIHGGSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VHWGQGTQVTVSS 359.02B01 EVQLVESGGGLVQPGRSLTLSCAASTNIESNSPMGWYRQAPGKQRELVAAIHGRSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VMWGQGTQVTVSS 360.02E03 EVQLVESGGGLVQPGRSLTLSCAASTNIESNSPMGWYRQAPGKQRELVAAIHGPSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VTWGQGTQVTVSS 361.01D03 EVQLVESGGGLVQPGRSLTLSCAASTNIESNSPMGWYRQAPGKQRELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VRWGQGTQVTVSS 362.01D06 EVQLVESGGGLVQPGRSLTLSCAASTNIFSRSPMGWYRQAPGKQRELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VTWGQGTQVTVSS 363.01H04 EVQLVESGGGLVQPGRSLTLSCAASTNIFSKSPMGWYRQAPGKQRELVAAIHGQSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VTWGQGTQVTVSS 364.02B07 EVQLVESGGGLVQPGRSLTLSCAASTNIFSSSPMGWYRQAPGKQRELVAAIHGHSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VTWGQGTQVTVSS 365.01A08 EVQLVESGGGLVQPGRSLTLSCAASTNIFSSSPMGWYRQAPGKQRELVAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRK VYWGQGTQVTVSS 366.01B07 EVQLVESGGGLVQPGRSLTLSCAASTNIFSRSPMGWYRQAPGKQRELVAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGIYHPRN VYWGQGTQVTVSS 367.01E03 EVQLVESGGGLVQPGRSLTLSCAASTNIFSESPMGWYRQAPGKQRELVAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGTYHPRN VYWGQGTQVTVSS 368.02E05 EVQLVESGGGLVQPGRSLTLSCAASTNIFSVSPMGWYRQAPGKQRELVAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGKYHPRN VYWGQGTQVTVSS 369.02H04 EVQLVESGGGLVQPGRSLTLSCAASTNIFSVSPMGWYRQAPGKQRELVAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VYWGQGTQVTVSS 370.02A07 EVQLVESGGGLVQPGRSLTLSCAASTNIFSKSPMGWYRQAPGKQRELVAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRE VYWGQGTQVTVSS 371.01D05 EVQLVESGGGLVQPGRSLTLSCAASTNIFSDSPMGWYRQAPGKQRELVAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VYWGQGTQVTVSS 372.01E05 EVQLVESGGGLVQPGRSLTLSCAASTNIFSRSPMGWYRQAPGKQRELVAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGKYHPRN VYWGQGTQVTVSS 373.01E02 EVQLVESGGGLVQPGRSLTLSCAASTNIFSHSPMGWYRQAPGKQRELVAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGRYHPRN VYWGQGTQVTVSS 374.02C06 EVQLVESGGGLVQPGRSLTLSCAASTNIFSTSPMGWYRQAPGKQRELVAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 375.02E11 EVQLVESGGGLVQPGRSLTLSCAASTNIFSTSPMGWYRQAPGKQRELVAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VQWGQGTQVTVSS 376.01E06 EVQLVESGGGLVQPGRSLTLSCAASTNIFSLSPMGWYRQAPGKQRELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VYWGQGTQVTVSS 377.01A03 EVQLVESGGGLVQPGRSLTLSCAASTNIFSISPGGWYRQAPGKQRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VYWGQGTQVTVSS 378.02A11 EVQLVESGGGLVQPGRSLTLSCAASTNHFSISPMGWYRQAPGKQRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRV VYWGQGTQVTVSS 379.01D07 EVQLVESGGGLVQPGRSLTLSCAASTNIFSASPMGWYRQAPGKQRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VNWGQGTQVTVSS 380.01D10 EVQLVESGGGLVQPGRSLTLSCAASTNIFSASPMGWYRQAPGKQRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGRYHPRN VYWGQGTQVTVSS 381.01A07 EVQLVESGGGLVQPGRSLTLSCAASTNISSTSPMGWYRQAPGKQRELVAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 382.02E12 EVQLVESGGGLVQPGRSLTLSCAASTNIESISPMGWYRQAPGKQRELVAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 383.02B05 EVQLVESGGGLVQPGRSLTLSCAASTNIFSISPYGWYRQAPGKQRELVAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 384.01E04 EVQLVESGGGLVQPGRSLTLSCAASTNIASISPMGWYRQAPGKQRELVAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 385.02A05 EVQLVESGGGLVQPGRSLTLSCAASTNIASISPMGWYRQAPGKQRELVAAIHGKSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 386.02C03 EVQLVESGGGLVQPGRSLTLSCAASTNIASISPMGWYRQAPGKQRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 387.01E03 EVQLVESGGGLVQPGRSLTLSCAASTNITSISPMGWYRQAPGKQRELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 388.01H09 EVQLVESGGGLVQPGRSLTLSCAASTNIMSISPMGWYRQAPGKQRELVAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 389.02G05 EVQLVESGGGLVQPGRSLTLSCAASTNITSISPMGWYRQAPGKQRELVAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 390.01C01 EVQLVESGGGLVQPGRSLTLSCAASTNIVSISPMGWYRQAPGKQRELVAAIHGHSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 391.01D02 EVQLVESGGGLVQPGRSLTLSCAASTNIVSISPMGWYRQAPGKQRELVAAIHGKSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 392.02D09 EVQLVESGGGLVQPGRSLTLSCAASTNVVSISPMGWYRQAPGKQRELVAAIHGKSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPNN VYWGQGTQVTVSS 393.02C01 EVQLVESGGGLVQPGRSLTLSCAASTNIISISPMGWYRQAPGKQRELVAAIHGASTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 394.02G02 EVQLVESGGGLVQPGRSLTLSCAASTNIFSITPMGWYRQAPGKQRELVAAIHGASTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 395.01B05 EVQLVESGGGLVQPGRSLTLSCAASTNITSISPMGWYRQAPGKQRELVAAIHGFETLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 396.01G08 EVQLVESGGGLVQPGRSLTLSCAASTNIQSISPMGWYRQAPGKQRELVAAIHGFETLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 397.01H06 EVQLVESGGGLVQPGRSLTLSCAASTSDESISPMGWYRQAPGKQRELVAAIHGFETLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 398.01E04 EVQLVESGGGLVQPGRSLTLSCAASTNIDSISPMGWYRQAPGKQRELVAAIHGFQTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 399.01H08 EVQLVESGGGLVQPGRSLTLSCAASTNIMSISPMGWYRQAPGKQRELVAAIHGFSTVYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 400.02E07 EVQLVESGGGLVQPGRSLTLSCAASTNIESISPMGWYRQAPGKQRELVAAIHGFSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 401.01C05 EVQLVESGGGLVQPGRSLTLSCAASTNIFSSSPMGWYRQAPGKQRELVAAIHGFKTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTARYYCNKVPWGDYHPGN VYWGQGTQVTVSS 402.02E04 EVQLVESGGGLVQPGRSLTLSCAASTNIFSSSPMGWYRQAPGKQRELVAAIHGFSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 403.02B06 EVQLVESGGGLVQPGRSLTLSCAASTNIESNSPMGWYRQAPGKQRELVAAIHGFSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 404.01E07 EVQLVESGGGLVQPGRSLTLSCAASTNIFSTSPMGWYRQAPGKQRELVAAIHGFSTIYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 405.02B04 EVQLVESGGGLVQPGRSLTLSCAASTNIFSTSPMGWYRQAPGKQRELVAAIHGFSTIYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPLN VYWGQGTQVTVSS 406.01H11 EVQLVESGGGLVQPGRSLTLSCVASTNIFSTSPMGWYRQAPGKQRELVAAIHGFSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 407.02E06 EVQLVESGGGLVQPGRSLTLSCAASTNIFSDSPMGWYRQAPGKQRELVAAIHGFSTFYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 408.01E08 EVQLVESGGGLVQPGRSLTLSCAASTNIFSQSPMGWYRQAPGKQRELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VCWGQGTQVTVSS 409.02A04 EVQLVESGGGLVQPGRSLTLSCAASTNIFSQSPMGWYRQAPGKQRELVAAIHGKSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPSN VYWGKGTQVTVSS 410.02A08 EVQLVESGGGLVQPGRSLTLSCAASTNIFSRSPMGWYRQAPGKQRELVAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGRYHPGN VYWGQGTQVTVSS 411.02E05 EVQLVESGGGLVQPGRSLTLSCAASTNIFSRSPMGWYRQAPGKQRELVAAIHGISTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 412.02H09 EVQLVESGGGLVQPGRSLTLSCAASTNIFSRSPMGWYRQAPGKQRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 413.02G06 EVQLVESGGGLVQPGRSLTLSCAASTNIFSGSPMGWYRQAPGKQRELVAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 414.01B09 EVQLVESGGGLVQPGRSLTLSCAASSNIFSISPMGWYRQAPGKQRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 415.02E03 EVQLVESGGGLVQPGRSLTLSCAASTNIFSIYPMGWYRQAPGKQRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPKN VYWGQGTQVTVSS 416.02E02 EVQLVESGGGLVQPGRSLTLSCAASTNIFSKSPMGWYRQAPGKQRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 417.02H01 EVQLVESGGGLVQPGRSLTLSCAASTNIFSKSPMGWYRQAPGKQRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VYWGQGTQVTVSS 418.01G10 EVQLVESGGGLVQPGRSLTLSCAASTNEFSISPMGWYRQAPGKQRELVAAIHGLSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGAYHPRN VYWGQGTQVTVSS 419.02D11 EVQLVESGGGLVQPGRSLTLSCAASTNEFSISPMGWYRQAPGKQRELVAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 420.01B01 EVQLVESGGGLVQPGRSLTLSCAASTNIPSISPMGWYRQAPGKQRELVAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VAWGQGTQVTVSS 421.01G11 EVQLVESGGGLVQPGRSLTLSCAASTNIPSISPMGWYRQAPGKQRELVAAIHGASTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VAWGQGTQVTVSS 422.01H10 EVQLVESGGGLVQPGRSLTLSCAASTNIPSISPMGWYRQAPGKQRELVAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VYWGQGTQVTVSS 423.01C04 EVQLVESGGGLVQPGRSLTLSCAASTNIPSISPMGWYRQAPGKQRELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VYWGQGTQVTVSS 424.01D04 EVQLVESGGGLVQPGRSLTLSCAASTNITSISPMGWYRQAPGKQRELVAAIHGVSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VQWGQGTQVTVSS 425.01E07 EVQLVESGGGLVQPGRSLTLSCAASTNIPSISPMGWYRQAPGKQRELVAAIHGQSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VQWGQGTQVTVSS 426.02B11 EVQLVESGGGLVQPGRSLTLSCAASTNIVSISPMGWYRQAPGKQRELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VSWGQGTQVTVSS 427.01E10 EVQLVESGGGLVQPGRSLTLSCAASSNIFSISPMGWYRQAPGKQRELVAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VTWGQGTQVTVSS 428.02G08 EVQLVESGGGLVQPGRSLTLSCAASTNIDSISPMGWYRQAPGKQRELVAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VTWGQGTQVTVSS 429.02G11 EVQLVESGGGLVQPGRSLTLSCAASTNIDSISPMGWYRQAPGKQRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VTWGQGTQVTVSS 430.02H06 EVQLVESGGGLVQPGRSLTLSCAASTNIRSISPMGWYRQAPGKQRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VVWGQGTQVTVSS 431.01B02 EVQLVESGGGLVQPGRSLTLSCAASTNITSISPMGWYRQAPGKQRELVAAISGFSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNEVPWGDYHPRN VYWGQGTQVTVSS 432.02H11 EVQLVESGGGLVQPGRSLTLSCAASTNITSISPMGWYRQAPGKQRELVAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VYWGQGTQVTVSS 433.01E08 EVQLVESGGGLVQPGRSLTLSCAASTNITSVSPMGWYRQAPGKQRELVAAIHGPSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPTN VYWGQGTQVTVSS 434.01H01 EVQLVESGGGLVQPGRSLTLSCAASTNIGSISPMGWYRQAPGKQRELVAAIHGQSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPQN VYWGQGTQVTVSS 435.01E10 EVQLVESGGGLVQPGRSLTLSCAASTNIESISPMGWYRQAPGKQRELVAAIHGKSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRR VYWGQGTQVTVSS 436.01G01 EVQLVESGGGLVQPGRSLTLSCAASTNIVSISPMGWYRQAPGKQRELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRR VYWGQGTQVTVSS 437.01G04 EVQLVESGGGLVQPGRSLTLSCAASTNIDSISPMGWYRQAPGKQRELVAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRM VYWGQGTQVTVSS 438.01A04 EVQLVESGGGLVQPGRSLTLSCAASTNIEMISPMGWYRQAPGKQRELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGRYHPRN VYWGQGTQVTVSS 439.01E12 EVQLVESGGGLVQPGRSLTLSCAASTNIFRISPMGWYRQAPGKQRELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGRYHPRN VYWGQGTQVTVSS 440.01B06 EVQLVESGGGLVQPGRSLTLSCAASTNIFSISPMGWYRQAPGKQRELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGEYHPRN VYWGQGTQVTVSS 441.01C06 EVQLVESGGGLVQPGRSLTLSCAASTNIFSISPMGWYRQAPGKQRELVAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGKYHPRN VYWGQGTQVTVSS 442.01B08 EVQLVESGGGLVQPGRSLTLSCAASTNIESISPMGWYRQAPGKQRELVAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGRYHPRN VYWGQGTQVTVSS 443.01C02 EVQLVESGGGLVQPGRSLTLSCAASTNIESISPMGWYRQAPGKQRELVAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGRYHPRN VYWGQGTQVTVSS 444.01C10 EVQLVESGGGLVQPGRSLTLSCAASTNISSTSPMGWYRQAPGKQRELVAAIHGFSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGYYHPRN VYWGQGTQVTVSS 445.01E09 EVQLVESGGGLVQPGRSLTLSCAASTNISSTSPMGWYRQAPGKQRELVAAIHGHSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGRYHPRN VYWGQGTQVTVSS 446.02D06 EVQLVESGGGLVQPGRSLTLSCAASTNISSTSPMGWYRQAPGKQRELVAAIHGFSTVYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGRYHPRN VYWGQGTQVTVSS 447.01A06 EVQLVESGGGLVQPGRSLTLSCAASTNIFSIRPMGWYRQAPGKQRELVAAIHGFSTVYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VYWGQGTQVTVSS 448.01C07 EVQLVESGGGLVQPGRSLTLSCAASTNIFSIYPMGWYRQAPGKQRELVAAIHGFSTYYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGSYHPRN VYWGQGTQVTVSS 449.01G09 EVQLVESGGGLVQPGRSLTLSCAASTNIFNISPMGWYRQAPGKQRELVAAIHGFSTYYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGRYHPRN VYWGQGTQVTVSS 450.01E05 EVQLVESGGGLVQPGRSLTLSCAASTNIFSSSPMGWYRQAPGKQRELVAAIHGFSTWYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGRYHPRN VYWGQGTQVTVSS 451.02B12 EVQLVESGGGLVQPGRSLTLSCAASTNISSTSPMGWYRQAPGKQRELVAAIHGFDTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VYWGQGTQVTVSS 452.02G01 EVQLVESGGGLVQPGRSLTLSCAASTNIFSINPMGWYRQAPGKQRELVAAIHGFDTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRN VSWGQGTQVTVSS 453.01A09 EVQLVESGGGLVQPGRSLTLSCAASTNIFSITPMGWYRQAPGKQRELVAAIHGRSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGSYHPRN VYWGQGTQVTVSS 454.01H05 EVQLVESGGGLVQPGRSLTLSCAASTNIFSITPMGWYRQAPGKQRELVAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGRYHPRN VYWGQGTQVTVSS 455.02E06 EVQLVESGGGLVQPGRSLTLSCAASTNIFSITPMGWYRQAPGKQRELVAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGRYHPRN VYWGQGTQVTVSS 456.02G07 EVQLVESGGGLVQPGRSLTLSCAASTNIFSITPMGWYRQAPGKQRELVAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPRD VYWGQGTQVTVSS 457.01E07- EVQLVESGGGLVQPGRSLTLSCAASTNIFSTSPYGWYRQAPGKQRELVAAIHG M34YFSTIYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 458.01E01- EVQLVESGGGLVQPGRSLTLSCAASTNIFSTSPGGWYRQAPGKQRELVAAIHG M34GFSTIYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 459.02G02- EVQLVESGGGLVQPGRSLTLSCAASTNIFSITPYGWYRQAPGKQRELVAAIHG M34YASTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 460.02G02- EVQLVESGGGLVQPGRSLTLSCAASTNIFSITPGGWYRQAPGKQRELVAAIHG M34GASTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYCNKVPWGDYHPGN VYWGQGTQVTVSS 461.F1 EVQLVESGGGLVQPGRSLTLSCAAS 462. F1 EVQLVESGGGLVQPGRSLTLSCVAS 463. F2WYRQAPGKQRELVA 464. F3 GRFTISRDNAKNSIYLQMNSLRPEDTALYYCNK 465. F3GRFTISRDNAKNSIYLQMNSLRPEDTALYYCNE 466. F4 WGQGTQVTVSS 467. F4WGKGTQVTVSS 468. HumanMLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTN BCMAAILWTCLGLSLIISLAVEVLMELLRKINSEPLKDEFKNTGSGLLGMANIDLEKSRTGDEIILPRGLEYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTTKTNDYCKSLPAALSATEIEKSISAR 469. MurineMAQQCFHSEYFDSLLHACKPCHLRCSNPPATCQPYCDPSVTSSVKGTYTVLWI BCMAFLGLTLVLSLALFTISELLRKMNPEALKDEPQSPGQLDGSAQLDKADTELTRIRAGDDRIFPRSLEYTVEECTCEDCVKSKPKGDSDHFFPLPAMEEGATILVTTKTGDYGKSSVPTALQSVMGMEKPTHTR 470. CynomolgusMLQMARQCSQNEYFDSLLHDCKPCQLRCSSTPPLTCQRYCNASMTNSVKGMNA BCMAILWTCLGLSLIISLAVEVLTELLRKMSSEPLKDEFKNTGSGLLGMANIDLEKGRTGDEIVLPRGLEYTVEECTCEDCIKNKPKVDSDHCFPLPAMEEGATILVTTKTNDYCNSLSAALSVTEIEKSISAR 471. 6x His His-His-His-His-His-His tag SEQConstruct ID NO Name Sequence 472. Exemplary (GS)n linker sequence 473.Exemplary (GGS)n linker sequence 474. Exemplary (GGGS)n linker sequence475. Exemplary (GGSG)n linker sequence 476. Exemplary (GGSGG)nlinker sequence 477. Exemplary (GGGGS)n linker sequence 478. Exemplary(GGGGG)n linker sequence 479. Exemplary (GGG)n linker sequence 480.Exemplary (GGGGS)4 linker sequence 481. Exemplary (GGGGS)3linker sequence 482. Exemplary LPETG linker sequence 483. Exemplary BH2TEVQLVESGGGLVQPGRSLTLSCAASTNIFSISPMGWYRQAPGKQREL TriTAC ™VAAIHGFSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 484. Exemplary 01A01EVQLVESGGGLVQPGRSLTLSCAASTDIFSISPMGWYRQAPGKQREL TriTAC ™VAAIHGGSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVAWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 485. Exemplary 02E09EVQLVESGGGLVQPGRSLTLSCAASTNDFSISPMGWYRQAPGKQREL TriTAC ™VAAIHGGSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVAWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 486. Exemplary 01B03EVQLVESGGGLVQPGRSLTLSCAASTNIFSKSPMGWYRQAPGKQREL TriTAC ™VAAIHGKSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVVWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 487. Exemplary 01B04EVQLVESGGGLVQPGRSLTLSCAASTNDFSISPMGWYRQAPGKQREL TriTAC ™VAAIHGKSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVKWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 488. Exemplary 02H05EVQLVESGGGLVQPGRSLTLSCAASTNQFSISPMGWYRQAPGKQREL TriTAC ™VAAIHGKSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVVWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 489. Exemplary 01A02EVQLVESGGGLVQPGRSLTLSCAASTNIFSSSPMGWYRQAPGKQREL TriTAC ™VAAINGFSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVHWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 490. Exemplary 01A05EVQLVESGGGLVQPGRSLTLSCAASTNIFSSSPMGWYRQAPGKQREL TriTAC ™VAAIHGFSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 491. Exemplary 01B12EVQLVESGGGLVQPGRSLTLSCAASTNIFSTSPMGWYRQAPGKQREL TriTAC ™VAAIHGFQTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVVWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 492. Exemplary 01G06EVQLVESGGGLVQPGRSLTLSCAASTNIFSRSPMGWYRQAPGKQREL TriTAC ™VAAIHGFETLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVLWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 493. Exemplary 02C05EVQLVESGGGLVQPGRSLTLSCAASTNIFSESPMGWYRQAPGKQREL TriTAC ™VAAIHGFTTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVTWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 494. Exemplary 02G09EVQLVESGGGLVQPGRSLTLSCAASTNIFSDSPMGWYRQAPGKQREL TriTAC ™VAAIHGFSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVAWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 495. Exemplary 01C08EVQLVESGGGLVQPGRSLTLSCAASTNIFSNSPMGWYRQAPGKQREL TriTAC ™VAAIHGGSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVHWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 496. Exemplary 02B01EVQLVESGGGLVQPGRSLTLSCAASTNIFSNSPMGWYRQAPGKQREL TriTAC ™VAAIHGRSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVMWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 497. Exemplary 02E03EVQLVESGGGLVQPGRSLTLSCAASTNIFSNSPMGWYRQAPGKQREL TriTAC ™VAAIHGPSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVTWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 498. Exemplary 01D03EVQLVESGGGLVQPGRSLTLSCAASTNIFSNSPMGWYRQAPGKQREL TriTAC ™VAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVRWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 499. Exemplary 01D06EVQLVESGGGLVQPGRSLTLSCAASTNIFSRSPMGWYRQAPGKQREL TriTAC ™VAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVTWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 500. Exemplary 01H04EVQLVESGGGLVQPGRSLTLSCAASTNIFSKSPMGWYRQAPGKQREL TriTAC ™VAAIHGQSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVTWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 501. Exemplary 02B07EVQLVESGGGLVQPGRSLTLSCAASTNIFSSSPMGWYRQAPGKQREL TriTAC ™VAAIHGHSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVTWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 502. Exemplary 01A08EVQLVESGGGLVQPGRSLTLSCAASTNIFSSSPMGWYRQAPGKQREL TriTAC ™VAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRKVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 503. Exemplary 01B07EVQLVESGGGLVQPGRSLTLSCAASTNIFSRSPMGWYRQAPGKQREL TriTAC ™VAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGIYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 504. Exemplary 01E03EVQLVESGGGLVQPGRSLTLSCAASTNIFSESPMGWYRQAPGKQREL TriTAC ™VAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGTYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 505. Exemplary 02E05EVQLVESGGGLVQPGRSLTLSCAASTNIFSVSPMGWYRQAPGKQREL TriTAC ™VAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGKYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 506. Exemplary 02H04EVQLVESGGGLVQPGRSLTLSCAASTNIFSVSPMGWYRQAPGKQREL TriTAC ™VAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 507. Exemplary 02A07EVQLVESGGGLVQPGRSLTLSCAASTNIFSKSPMGWYRQAPGKQREL TriTAC ™VAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPREVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 508. Exemplary 01D05EVQLVESGGGLVQPGRSLTLSCAASTNIFSDSPMGWYRQAPGKQREL TriTAC ™VAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 509. Exemplary 01E05EVQLVESGGGLVQPGRSLTLSCAASTNIFSRSPMGWYRQAPGKQREL TriTAC ™VAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGKYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 510. Exemplary 01E02EVQLVESGGGLVQPGRSLTLSCAASTNIFSHSPMGWYRQAPGKQREL TriTAC ™VAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGRYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 511. Exemplary 02C06EVQLVESGGGLVQPGRSLTLSCAASTNIFSTSPMGWYRQAPGKQREL TriTAC ™VAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 512. Exemplary 02E11EVQLVESGGGLVQPGRSLTLSCAASTNIFSTSPMGWYRQAPGKQREL TriTAC ™VAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVQWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 513. Exemplary 01E06EVQLVESGGGLVQPGRSLTLSCAASTNIFSLSPMGWYRQAPGKQREL TriTAC ™VAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 514. Exemplary 01A03EVQLVESGGGLVQPGRSLTLSCAASTNIFSISPGGWYRQAPGKQREL TriTAC ™VAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 515. Exemplary 02A11EVQLVESGGGLVQPGRSLTLSCAASTNHFSISPMGWYRQAPGKQREL TriTAC ™VAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRVVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 516. Exemplary 01D07EVQLVESGGGLVQPGRSLTLSCAASTNIFSASPMGWYRQAPGKQREL TriTAC ™VAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVNWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 517. Exemplary 01D10EVQLVESGGGLVQPGRSLTLSCAASTNIFSASPMGWYRQAPGKQREL TriTAC ™VAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGRYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 518. Exemplary 01A07EVQLVESGGGLVQPGRSLTLSCAASTNISSISPMGWYRQAPGKQREL TriTAC ™VAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 519. Exemplary 02E12EVQLVESGGGLVQPGRSLTLSCAASTNIESISPMGWYRQAPGKQREL TriTAC ™VAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 520. Exemplary 02B05EVQLVESGGGLVQPGRSLTLSCAASTNIFSISPYGWYRQAPGKQREL TriTAC ™VAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 521. Exemplary 01E04EVQLVESGGGLVQPGRSLTLSCAASTNIASISPMGWYRQAPGKQREL TriTAC ™VAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 522. Exemplary 02A05EVQLVESGGGLVQPGRSLTLSCAASTNIASISPMGWYRQAPGKQREL TriTAC ™VAAIHGKSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 523. Exemplary 02C03EVQLVESGGGLVQPGRSLTLSCAASTNIASISPMGWYRQAPGKQREL TriTAC ™VAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 524. Exemplary 01E03EVQLVESGGGLVQPGRSLTLSCAASTNITSISPMGWYRQAPGKQREL TriTAC ™VAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 525. Exemplary 01H09EVQLVESGGGLVQPGRSLTLSCAASTNIMSISPMGWYRQAPGKQREL TriTAC ™VAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 526. Exemplary 02G05EVQLVESGGGLVQPGRSLTLSCAASTNITSISPMGWYRQAPGKQREL TriTAC ™VAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 527. Exemplary 01C01EVQLVESGGGLVQPGRSLTLSCAASTNIVSISPMGWYRQAPGKQREL TriTAC ™VAAIHGHSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 528. Exemplary 01D02EVQLVESGGGLVQPGRSLTLSCAASTNIVSISPMGWYRQAPGKQREL TriTAC ™VAAIHGKSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 529. Exemplary 02D09EVQLVESGGGLVQPGRSLTLSCAASTNVVSISPMGWYRQAPGKQREL TriTAC ™VAAIHGKSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPNNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 530. Exemplary 02C01EVQLVESGGGLVQPGRSLTLSCAASTNIISISPMGWYRQAPGKQREL TriTAC ™VAAIHGASTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 531. Exemplary 02G02EVQLVESGGGLVQPGRSLTLSCAASTNIFSITPMGWYRQAPGKQREL TriTAC ™VAAIHGASTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 532. Exemplary 01B05EVQLVESGGGLVQPGRSLTLSCAASTNITSISPMGWYRQAPGKQREL TriTAC ™VAAIHGFETLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 533. Exemplary 01G08EVQLVESGGGLVQPGRSLTLSCAASTNIQSISPMGWYRQAPGKQREL TriTAC ™VAAIHGFETLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 534. Exemplary 01H06EVQLVESGGGLVQPGRSLTLSCAASTSDFSISPMGWYRQAPGKQREL TriTAC ™VAAIHGFETLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 535. Exemplary 01E04EVQLVESGGGLVQPGRSLTLSCAASTNIDSISPMGWYRQAPGKQREL TriTAC ™VAAIHGFQTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 536. Exemplary 01H08EVQLVESGGGLVQPGRSLTLSCAASTNIMSISPMGWYRQAPGKQREL TriTAC ™VAAIHGFSTVYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 537. Exemplary 02E07EVQLVESGGGLVQPGRSLTLSCAASTNIESISPMGWYRQAPGKQREL TriTAC ™VAAIHGFSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 538. Exemplary 01C05EVQLVESGGGLVQPGRSLTLSCAASTNIFSSSPMGWYRQAPGKQREL TriTAC ™VAAIHGFKTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTARYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 539. Exemplary 02E04EVQLVESGGGLVQPGRSLTLSCAASTNIFSSSPMGWYRQAPGKQREL TriTAC ™VAAIHGFSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 540. Exemplary 02B06EVQLVESGGGLVQPGRSLTLSCAASTNIFSNSPMGWYRQAPGKQREL TriTAC ™VAAIHGFSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 541. Exemplary 01E07EVQLVESGGGLVQPGRSLTLSCAASTNIFSTSPMGWYRQAPGKQREL TriTAC ™VAAIHGFSTIYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 542. Exemplary 02B04EVQLVESGGGLVQPGRSLTLSCAASTNIFSTSPMGWYRQAPGKQREL TriTAC ™VAAIHGFSTIYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPLNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 543. Exemplary 01H11EVQLVESGGGLVQPGRSLTLSCVASTNIFSTSPMGWYRQAPGKQREL TriTAC ™VAAIHGFSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 544. Exemplary 02E06EVQLVESGGGLVQPGRSLTLSCAASTNIFSDSPMGWYRQAPGKQREL TriTAC ™VAAIHGFSTFYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 545. Exemplary 01E08EVQLVESGGGLVQPGRSLTLSCAASTNIFSQSPMGWYRQAPGKQREL TriTAC ™VAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVCWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 546. Exemplary 02A04EVQLVESGGGLVQPGRSLTLSCAASTNIFSQSPMGWYRQAPGKQREL TriTAC ™VAAIHGKSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPSNVYWGKGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 547. Exemplary 02A08EVQLVESGGGLVQPGRSLTLSCAASTNIFSRSPMGWYRQAPGKQREL TriTAC ™VAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGRYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 548. Exemplary 02E05EVQLVESGGGLVQPGRSLTLSCAASTNIFSRSPMGWYRQAPGKQREL TriTAC ™VAAIHGISTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 549. Exemplary 02H09EVQLVESGGGLVQPGRSLTLSCAASTNIFSRSPMGWYRQAPGKQREL TriTAC ™VAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 550. Exemplary 02G06EVQLVESGGGLVQPGRSLTLSCAASTNIFSGSPMGWYRQAPGKQREL TriTAC ™VAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 551. Exemplary 01B09EVQLVESGGGLVQPGRSLTLSCAASSNIFSISPMGWYRQAPGKQREL TriTAC ™VAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 552. Exemplary 02E03EVQLVESGGGLVQPGRSLTLSCAASTNIFSIYPMGWYRQAPGKQREL TriTAC ™VAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPKNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 553. Exemplary 02E02EVQLVESGGGLVQPGRSLTLSCAASTNIFSKSPMGWYRQAPGKQREL TriTAC ™VAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 554. Exemplary 02H01EVQLVESGGGLVQPGRSLTLSCAASTNIFSKSPMGWYRQAPGKQREL TriTAC ™VAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 555. Exemplary 01G10EVQLVESGGGLVQPGRSLTLSCAASTNEFSISPMGWYRQAPGKQREL TriTAC ™VAAIHGLSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGAYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 556. Exemplary 02D11EVQLVESGGGLVQPGRSLTLSCAASTNEFSISPMGWYRQAPGKQREL TriTAC ™VAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 557. Exemplary 01B01EVQLVESGGGLVQPGRSLTLSCAASTNIPSISPMGWYRQAPGKQREL TriTAC ™VAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVAWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 558. Exemplary 01G11EVQLVESGGGLVQPGRSLTLSCAASTNIPSISPMGWYRQAPGKQREL TriTAC ™VAAIHGASTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVAWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 559. Exemplary 01H10EVQLVESGGGLVQPGRSLTLSCAASTNIPSISPMGWYRQAPGKQREL TriTAC ™VAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 560. Exemplary 01C04EVQLVESGGGLVQPGRSLTLSCAASTNIPSISPMGWYRQAPGKQREL TriTAC ™VAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 561. Exemplary 01D04EVQLVESGGGLVQPGRSLTLSCAASTNITSISPMGWYRQAPGKQREL TriTAC ™VAAIHGVSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVQWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 562. Exemplary 01E07EVQLVESGGGLVQPGRSLTLSCAASTNIPSISPMGWYRQAPGKQREL TriTAC ™VAAIHGQSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVQWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 563. Exemplary 02B11EVQLVESGGGLVQPGRSLTLSCAASTNIVSISPMGWYRQAPGKQREL TriTAC ™VAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVSWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 564. Exemplary 01E10EVQLVESGGGLVQPGRSLTLSCAASSNIFSISPMGWYRQAPGKQREL TriTAC ™VAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVTWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVEGGG TKLTVLHHHHHH 565.Exemplary 02G08 EVQLVESGGGLVQPGRSLTLSCAASTNIDSISPMGWYRQAPGKQREL TriTAC ™VAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVTWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 566. Exemplary 02G11EVQLVESGGGLVQPGRSLTLSCAASTNIDSISPMGWYRQAPGKQREL TriTAC ™VAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVTWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 567. Exemplary 02H06EVQLVESGGGLVQPGRSLTLSCAASTNIRSISPMGWYRQAPGKQREL TriTAC ™VAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVVWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 568. Exemplary 01B02EVQLVESGGGLVQPGRSLTLSCAASTNITSISPMGWYRQAPGKQREL TriTAC ™VAAISGFSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNEVPWGDYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 569. Exemplary 02H11EVQLVESGGGLVQPGRSLTLSCAASTNITSISPMGWYRQAPGKQREL TriTAC ™VAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 570. Exemplary 01E08EVQLVESGGGLVQPGRSLTLSCAASTNITSVSPMGWYRQAPGKQREL TriTAC ™VAAIHGPSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPTNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 571. Exemplary 01H01EVQLVESGGGLVQPGRSLTLSCAASTNIGSISPMGWYRQAPGKQREL TriTAC ™VAAIHGQSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPQNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 572. Exemplary 01E10EVQLVESGGGLVQPGRSLTLSCAASTNIESISPMGWYRQAPGKQREL TriTAC ™VAAIHGKSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRRVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 573. Exemplary 01G01EVQLVESGGGLVQPGRSLTLSCAASTNIVSISPMGWYRQAPGKQREL TriTAC ™VAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRRVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 574. Exemplary 01G04EVQLVESGGGLVQPGRSLTLSCAASTNIDSISPMGWYRQAPGKQREL TriTAC ™VAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRMVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 575. Exemplary 01A04EVQLVESGGGLVQPGRSLTLSCAASTNIFMISPMGWYRQAPGKQREL TriTAC ™VAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGRYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 576. Exemplary 01E12EVQLVESGGGLVQPGRSLTLSCAASTNIFRISPMGWYRQAPGKQREL TriTAC ™VAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGRYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 577. Exemplary 01B06EVQLVESGGGLVQPGRSLTLSCAASTNIFSISPMGWYRQAPGKQREL TriTAC ™VAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGEYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 578. Exemplary 01C06EVQLVESGGGLVQPGRSLTLSCAASTNIFSISPMGWYRQAPGKQREL TriTAC ™VAAIHGDSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGKYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 579. Exemplary 01B08EVQLVESGGGLVQPGRSLTLSCAASTNIESISPMGWYRQAPGKQREL TriTAC ™VAAIHGSSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGRYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 580. Exemplary 01CO2EVQLVESGGGLVQPGRSLTLSCAASTNIESISPMGWYRQAPGKQREL TriTAC ™VAAIHGNSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGRYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 581. Exemplary 01C10EVQLVESGGGLVQPGRSLTLSCAASTNISSISPMGWYRQAPGKQREL TriTAC ™VAAIHGFSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGYYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 582. Exemplary 01E09EVQLVESGGGLVQPGRSLTLSCAASTNISSISPMGWYRQAPGKQREL TriTAC ™VAAIHGHSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGRYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 583. Exemplary 02D06EVQLVESGGGLVQPGRSLTLSCAASTNISSISPMGWYRQAPGKQREL TriTAC ™VAAIHGFSTVYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGRYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 584. Exemplary 01A06EVQLVESGGGLVQPGRSLTLSCAASTNIFSIRPMGWYRQAPGKQREL TriTAC ™VAAIHGFSTVYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 585. Exemplary 01C07EVQLVESGGGLVQPGRSLTLSCAASTNIFSIYPMGWYRQAPGKQREL TriTAC ™VAAIHGFSTYYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGSYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 586. Exemplary 01G09EVQLVESGGGLVQPGRSLTLSCAASTNIFNISPMGWYRQAPGKQREL TriTAC ™VAAIHGFSTYYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGRYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 587. Exemplary 01E05EVQLVESGGGLVQPGRSLTLSCAASTNIFSSSPMGWYRQAPGKQREL TriTAC ™VAAIHGFSTWYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGRYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 588. Exemplary 02B12EVQLVESGGGLVQPGRSLTLSCAASTNISSISPMGWYRQAPGKQREL TriTAC ™VAAIHGFDTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 589. Exemplary 02G01EVQLVESGGGLVQPGRSLTLSCAASTNIFSINPMGWYRQAPGKQREL TriTAC ™VAAIHGFDTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRNVSWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 590. Exemplary 01A09EVQLVESGGGLVQPGRSLTLSCAASTNIFSITPMGWYRQAPGKQREL TriTAC ™VAAIHGRSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGSYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 591. Exemplary 01H05EVQLVESGGGLVQPGRSLTLSCAASTNIFSITPMGWYRQAPGKQREL TriTAC ™VAAIHGTSTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGRYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 592. Exemplary 02E06EVQLVESGGGLVQPGRSLTLSCAASTNIFSITPMGWYRQAPGKQREL TriTAC ™VAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGRYHPRNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 593. Exemplary 02G07EVQLVESGGGLVQPGRSLTLSCAASTNIFSITPMGWYRQAPGKQREL TriTAC ™VAAIHGESTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC sequenceNKVPWGDYHPRDVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 594. ExemplaryEVQLVESGGGLVQPGRSLTLSCAASTNIFSTSPYGWYRQAPGKQREL 01F07-M34YVAAIHGFSTIYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC TriTAC ™NKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQ sequencePGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 595. ExemplaryEVQLVESGGGLVQPGRSLTLSCAASTNIFSTSPGGWYRQAPGKQREL 01F01-M34GVAAIHGFSTIYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC TriTAC ™NKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQ sequencePGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 596. ExemplaryEVQLVESGGGLVQPGRSLTLSCAASTNIFSITPYGWYRQAPGKQREL 02G02-M34YVAAIHGASTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC TriTAC ™NKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQ sequencePGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 597. ExemplaryEVQLVESGGGLVQPGRSLTLSCAASTNIFSITPGGWYRQAPGKQREL 02G02-M34GVAAIHGASTLYADSVKGRFTISRDNAKNSIYLQMNSLRPEDTALYYC TriTAC ™NKVPWGDYHPGNVYWGQGTQVTVSSGGGGSGGGSEVQLVESGGGLVQ sequencePGNSLRLSCAASGFTFSKFGMSWVRQAPGKGLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSSGGGGSGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAINWVRQAPGKGLEWVARIRSKYNNYATYYADQVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHANFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCASSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLVPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCTLWYSNRWVFGGGTKLTVLHHHHHH 598. 253BH10 (llamaQVQLVESGGGLVQPGESLRLSCAASTNIFSISPMGWYRQAPGKQREL anti-BCMAVAAIHGFSTLYADSVKGRFTISRDNAKNTIYLQMNSLKPEDTAVYYC antibody)NKVPWGDYHPRNVYWGQGTQVTVSS 599. 253BH10 CDR1 TNIFSISPMG 600. 253BH10 CDR2AIHGFSTLYADSVK 601. 253BH10 CDR3 VPWGDYHPRNVY

1.-30. (canceled)
 31. A method for treating a cancer in a subject inneed thereof, comprising administering to the subject a pharmaceuticalcomposition comprising a B cell maturation agent (BCMA) bindingtrispecific protein that comprises: (a) a first domain (A) thatspecifically binds to a human CD3; (b) a second domain (B) thatspecifically binds to a human serum albumin protein; and (c) a thirddomain (C) that specifically binds to a human BCMA, wherein the thirddomain comprises complementarity determining regions CDR1, CDR2, andCDR3, wherein the CDR1 comprises the amino acid sequence of SEQ ID No.76, the CDR2 comprises the amino acid sequence of SEQ ID No. 190, andthe CDR3 comprises the amino acid sequence of SEQ ID No. 304, andwherein the cancer is associated with BCMA.
 32. The method of claim 31,wherein the cancer is a leukemia, a lymphoma, a multiple myeloma, or ametastasis thereof.
 33. The method of claim 32, wherein the cancer isthe multiple myeloma.
 34. The method of claim 33, wherein the multiplemyeloma is a smoldering multiple myeloma, a non-secretory myeloma, or aosteosclerotic, myeloma.
 35. The method of claim 31, wherein the thirddomain comprises the following formula: f1-r1-f2-r2-f3-r3-f4, wherein,r1 is the CDR1; r2 is the CDR2; and r3 is the CDR3; and wherein f1, f2,f3 and f4 are framework residues selected so that said protein is fromabout 80% to about 99% identical to the amino acid sequence set forth inSEQ ID NO: 346 or SEQ ID NO:
 598. 36. The method of claim 35, wherein f1comprises SEQ ID NO: 461 or 462, f2 comprises SEQ ID NO: 463, f3comprises SEQ ID NO: 464 or 465, and f4 comprises SEQ ID NO: 466 or 467.37. The method of claim 31, wherein the BCMA binding trispecific proteinfurther comprises linkers L1 and L2, wherein the domains of the proteinare linked in the order H₂N-(A)-L1-(C)-L2-(B)-COOH,H₂N-(B)-L1-(A)-L2-(C)-COOH, H₂N-(C)-L1-(B)-L2-(A)-COOH,H₂N-(C)-L1-(A)-L2-(B)-COOH, H₂N-(A)-L1-(B)-L2-(C)-COOH orH₂N-(B)-L1-(C)-L2-(A)-COOH.
 38. The method of claim 37, wherein thedomains are linked in the order H₂N-(C)-L1-(B)-L2-(A)-COOH.
 39. Themethod of claim 31, wherein the third domain comprises a sequence thatis at least 80% identical to SEQ ID NO.
 383. 40. The method of claim 31,wherein the third domain comprises a sequence that is at least 90%identical to SEQ ID NO.
 383. 41. The method of claim 31, wherein thethird domain comprises a sequence that is at least 95% identical to SEQID NO.
 383. 42. The method of claim 31, wherein the third domaincomprises a sequence that is at least 99% identical to SEQ ID NO. 383.43. The method of claim 31, wherein the BCMA binding trispecific proteincomprises a sequence that is at least 80% identical to SEQ II) NO. 520.44. The method of claim 31, wherein the BCMA binding trispecific proteincomprises a sequence that is at least 90% identical to SEQ ID NO. 520.45. The method of claim 31, wherein the BCMA binding trispecific proteincomprises a sequence that is at least 95% identical to SEQ. ID NO. 520.46. The method of claim 31, wherein the BCMA binding trispecific proteincomprises a sequence that is at least 99% identical to SEQ ID NO. 520.47. The method of claim 31, wherein the BCMA binding trispecific proteinhas an elimination half-time of at least 12 hours.
 48. The method ofclaim 47, wherein the BCMA binding trispecific protein has anelimination half-time of at least 20 hours.
 49. The method of claim 31,wherein the BCMA binding trispecific protein is less than about 80 kDa.50. The method of claim 49, wherein the BCMA binding trispecific proteinis less than about 75 kDa.